As one of the major acetyltransferases in mammalian cells, p300 (also known as EP300) and its highly related protein CBP (also known as CREBBP), collectively termed p300/CBP, is characterized as a key regulator in gene transcription by modulating the acetylation of histones. In recent decades, proteomic analyses have revealed that p300 is also involved in the regulation of various cellular processes by acetylating many non-histone proteins. Among the identified substrates, some are key players involved in different autophagy steps, which together establish p300 as a master regulator of autophagy. Accumulating evidence has shown that p300 activity is controlled by many distinct cellular pathways to regulate autophagy in response to cellular or environmental stimuli. In addition, several small molecules have been shown to regulate autophagy by targeting p300, suggesting that manipulation of p300 activity is sufficient for controlling autophagy. Importantly, dysfunction of p300-regulated autophagy has been implicated in a number of human disorders, such as cancer, aging and neurodegeneration, highlighting p300 as a promising target for the drug development of autophagy-related human disorders. Here, we focus on the roles of p300-mediated protein acetylation in the regulation of autophagy and discuss implications for autophagy-related human disorders.

Autophagy is a highly conserved lysosome-dependent degradation pathway in eukaryotic cells (Nakatogawa, 2020; Yim and Mizushima, 2020). According to the routes of cargo delivery to lysosomes, autophagy is typically classified into macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) (Yim and Mizushima, 2020) (Fig. 1). Macroautophagy depends on a series of membrane events, through which the phagophore expands to form the double-membrane autophagosome and sequesters intracellular materials, such as protein aggregates, damaged organelles and invading pathogens, and delivers them to lysosome for digestion (Yu et al., 2018; Zhao et al., 2021). Microautophagy requires membrane invagination at the surface of late endosomes or lysosomes, through which cellular materials can be directly delivered to lysosomes for degradation (Wang et al., 2023). Of note, only proteins are substrates of CMA (Kaushik and Cuervo, 2018). Here, KFERQ-like motifs present in some proteins, are first recognized by the chaperone heat shock cognate 70 kDa protein (HSC70; also known as HSPA8). After that, HSC70 bound to the target proteins interacts with lysosomal associated membrane protein 2A (LAMP2A) (Kaushik and Cuervo, 2018), before the target finally translocates into the lysosome through the channel formed by LAMP2A (Kaushik and Cuervo, 2018).

Fig. 1.

Types of autophagy in mammalian cells. Macroautophagy requires the de novo formation of double-membrane autophagosomes, which engulf cellular materials, such as proteins or organelles, and deliver them to lysosome for degradation. Chaperone-mediated autophagy (CMA) is responsible for the degradation of proteins that harbor KFERQ-like motifs. These are recognized by the chaperone HSC70 and transported across the lysosomal membrane through a channel composed of LAMP2A. Microautophagy is characterized by the direct uptake of cytoplasmic substrates, which depends on membrane invagination at the surface of late endosomes or lysosomes. All these types of autophagy culminate in lysosomal degradation and are required for the maintenance of cellular homeostasis.

Fig. 1.

Types of autophagy in mammalian cells. Macroautophagy requires the de novo formation of double-membrane autophagosomes, which engulf cellular materials, such as proteins or organelles, and deliver them to lysosome for degradation. Chaperone-mediated autophagy (CMA) is responsible for the degradation of proteins that harbor KFERQ-like motifs. These are recognized by the chaperone HSC70 and transported across the lysosomal membrane through a channel composed of LAMP2A. Microautophagy is characterized by the direct uptake of cytoplasmic substrates, which depends on membrane invagination at the surface of late endosomes or lysosomes. All these types of autophagy culminate in lysosomal degradation and are required for the maintenance of cellular homeostasis.

Macroautophagy (hereafter called autophagy) can be divided into several major steps, including autophagy initiation, membrane nucleation, formation of double-membrane autophagosomes and autophagosome-lysosome fusion; these are tightly controlled spatiotemporally by the autophagy machinery that consists of a large number of so-called autophagy-related genes (ATGs) (Yu et al., 2018; Zhao et al., 2021). Depending on the contents sequestered into autophagosomes, autophagy can be nonselective, also called bulk autophagy, or highly selective, known as selective autophagy, which includes aggrephagy, mitophagy, ribophagy and xenophagy among others (Lamark and Johansen, 2021; Vargas et al., 2023). As an important pathway for maintaining cellular homeostasis, autophagy is dysregulated in a number of major human disorders, including many types of cancers (Klionsky et al., 2021; Mizushima and Levine, 2020).

In mammalian cells, E1A-binding protein p300 (also known as EP300) and the highly related CREB-binding protein (also known as CREBBP), collectively often termed p300/CBP in the literature (unless otherwise specified, we use p300 hereafter to refer to both p300 and CBP for simplicity), were originally identified as transcription co-activators that increase the transcriptional activity of specific transcription factors by binding and bridging them to the transcription machinery (Arany et al., 1994; Lundblad et al., 1995). Later studies revealed that the function of p300 in transcription can also be attributed to its acetyltransferase activity (Bannister and Kouzarides, 1996; Ogryzko et al., 1996). Acetylation of histones by p300 decreases their affinity to DNA by removing a positive charge. Consequently, the condensed chromatin is converted into a more relaxed form, which facilitates its accessibility to transcription-related proteins and leads to activation of transcription (Chan and La Thangue, 2001; Dancy and Cole, 2015). Of note, protein acetylation is a highly dynamic and reversible process, which is exerted by two classes of enzymes, acetyltransferases and deacetylases (Narita et al., 2019; Verdin and Ott, 2015). Acetyltransferases mediate the addition of the acetyl group, derived from acetyl-coenzyme A (acetyl-CoA), to the lysine residues of the substrates (Narita et al., 2019; Verdin and Ott, 2015). By contrast, deacetylases catalyze the removal of the acetyl group from the modified lysine residues (Narita et al., 2019; Verdin and Ott, 2015). In the past two decades, protein acetylation has been demonstrated to be a key regulation mechanism in a variety of physiological processes, such as cell growth, cell differentiation and cell death, as it tightly controls the function of a large number of proteins (Menzies et al., 2016; Shvedunova and Akhtar, 2022; Xu and Wan, 2023).

Accumulating evidence suggests that protein acetylation is involved in the regulation of autophagy by modifying many key proteins that function in different steps of autophagy (McEwan and Dikic, 2011; Son et al., 2021; Xu and Wan, 2023). Most of the identified substrates are targets of p300 (Huang et al., 2015; Lee and Finkel, 2009; Shen et al., 2021; Su et al., 2017; Sun et al., 2022, 2015; Yi et al., 2022), highlighting p300 as a pivotal regulator of autophagy. Various cellular signaling pathways, as well as some small molecules, have been reported to control p300 activity and to regulate autophagy (Chen et al., 2007b; Huang and Chen, 2005; Marcu et al., 2006; Marino et al., 2014; Pietrocola et al., 2018; Pietrocola et al., 2015; Wan et al., 2017; Xu et al., 2020; Yang et al., 2001). In addition, dysregulation of p300 activity and dysfunction of p300-mediated autophagy are implicated in the pathogenesis of some major human disorders (Cheng et al., 2017; Lu et al., 2014; Pasqualucci et al., 2011; Suganuma et al., 2002).

In this Review, we aim to summarize the current knowledge on the versatile role of p300 in autophagy, the regulation of p300 activity by cellular pathways and small molecules, and to emphasize the implication of p300-regulated autophagy in human disorders. By focusing on recent findings, we highlight p300 as a master regulator of autophagy and autophagy-related physiological or pathophysiological processes.

Autophagy is a sequential process, and its different steps are tightly controlled by distinct proteins; many of these have been identified as p300 substrates as outlined below.

Autophagy initiation and membrane nucleation

The Unc-51 like autophagy activating kinase 1 (ULK1) complex and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3, also called VPS34) complex 1 are two major upstream protein complexes that function in autophagy initiation and membrane nucleation (Feng et al., 2014; Yin et al., 2016) (Fig. 2). Upon upstream signaling, such as activation of AMP-activated protein kinase (AMPK) or inactivation of the mechanistic target of rapamycin kinase (mTOR) complex 1 (mTORC1), the ULK1 complex upregulates activity of the PIK3C3 complex 1, which is responsible for the local synthesis of phosphatidylinositol-3-phosphate (PtdIns3P) at the endoplasmic reticulum (ER), for autophagy initiation (Boya et al., 2013; King et al., 2021; Russell et al., 2014).

Fig. 2.

Overview of the role of p300/CBP in autophagy regulation. Upon autophagic stimuli, the ULK1 complex is activated, leading to an increase of the activity of PIK3C3 complex 1 and the subsequent synthesis of phosphatidylinositol-3-phosphate (PtdIns3P) at the ER, which recruits downstream effectors to initiate autophagosome formation. CBP but not p300 acetylates RB1CC1 (also known as FIP200), an obligatory subunit of the ULK1 complex, to promote autophagy induction by preventing its ubiquitylation and subsequent proteasomal degradation. p300-mediated acetylation of BECN1 and PIK3C3, two essential subunits of the PIK3C3 complex 1, inhibits autophagy initiation by decreasing its activity. LC3 lipidation is required for the phagophore to expand into an autophagosomes and to recruit autophagy substrates. Through the action of the E1-like enzyme ATG7 and E2-like enzyme ATG10, ATG12 is conjugated to ATG5 to form a ATG12–ATG5 subcomplex, which is then assembled into the ATG12–ATG5-ATG16L1 complex though a direct association between ATG5 and ATG16L1. ATG12–ATG5-ATG16L1 is recruited to the phagophore by its interacting partner WIPI2, which binds to PtdIns3P at the phagophore. Full-length LC3 is cleaved by the protease ATG4 to expose its C-terminal G120, which is covalently conjugated to lipid phosphatidylethanolamine (PE) by the E1-like ATG7, E2-like ATG3 and the E3-like ATG12–ATG5-ATG16L1 complex. Several factors involved in LC3 lipidation are also regulated by p300-mediated acetylation. Acetylation of ATG4 by p300 inhibits its interaction with full-length LC3, leading to decreased LC3 cleavage. LC3, ATG5, ATG7 and ATG12 are also p300 substrates. For instance, acetylation of LC3 inhibits its lipidation and subsequent autophagosome formation. Autophagosome–lysosome fusion is tightly controlled by SNARE proteins. Autophagosome-localized STX17 recruits SNAP29 to form the STX17–SNAP29 subcomplex (bottom right), which then assembles into the trimeric SNARE complex by binding to lysosome-localized SNARE protein VAMP8. CBP but not p300 inhibits autophagosome-lysosome fusion by acetylating STX17; this decreases its interaction with SNAP29, inhibiting the formation of a functional SNARE complex.

Fig. 2.

Overview of the role of p300/CBP in autophagy regulation. Upon autophagic stimuli, the ULK1 complex is activated, leading to an increase of the activity of PIK3C3 complex 1 and the subsequent synthesis of phosphatidylinositol-3-phosphate (PtdIns3P) at the ER, which recruits downstream effectors to initiate autophagosome formation. CBP but not p300 acetylates RB1CC1 (also known as FIP200), an obligatory subunit of the ULK1 complex, to promote autophagy induction by preventing its ubiquitylation and subsequent proteasomal degradation. p300-mediated acetylation of BECN1 and PIK3C3, two essential subunits of the PIK3C3 complex 1, inhibits autophagy initiation by decreasing its activity. LC3 lipidation is required for the phagophore to expand into an autophagosomes and to recruit autophagy substrates. Through the action of the E1-like enzyme ATG7 and E2-like enzyme ATG10, ATG12 is conjugated to ATG5 to form a ATG12–ATG5 subcomplex, which is then assembled into the ATG12–ATG5-ATG16L1 complex though a direct association between ATG5 and ATG16L1. ATG12–ATG5-ATG16L1 is recruited to the phagophore by its interacting partner WIPI2, which binds to PtdIns3P at the phagophore. Full-length LC3 is cleaved by the protease ATG4 to expose its C-terminal G120, which is covalently conjugated to lipid phosphatidylethanolamine (PE) by the E1-like ATG7, E2-like ATG3 and the E3-like ATG12–ATG5-ATG16L1 complex. Several factors involved in LC3 lipidation are also regulated by p300-mediated acetylation. Acetylation of ATG4 by p300 inhibits its interaction with full-length LC3, leading to decreased LC3 cleavage. LC3, ATG5, ATG7 and ATG12 are also p300 substrates. For instance, acetylation of LC3 inhibits its lipidation and subsequent autophagosome formation. Autophagosome–lysosome fusion is tightly controlled by SNARE proteins. Autophagosome-localized STX17 recruits SNAP29 to form the STX17–SNAP29 subcomplex (bottom right), which then assembles into the trimeric SNARE complex by binding to lysosome-localized SNARE protein VAMP8. CBP but not p300 inhibits autophagosome-lysosome fusion by acetylating STX17; this decreases its interaction with SNAP29, inhibiting the formation of a functional SNARE complex.

RB1 inducible coiled-coil 1 (RB1CC1, also known as FIP200), one of the essential components of ULK1 complex, has recently been reported to be acetylated by CBP but not p300 (Yi et al., 2022) (Fig. 2; Table 1). Interestingly, K276 of RB1CC1, the major acetylation site targeted by CBP, can also be targeted by ubiquitylation (Yi et al., 2022). As a result, acetylation of RB1CC1 by CBP inhibits its ubiquitylation and subsequent proteasomal degradation; this stabilizes RB1CC1 and promotes initiation of autophagy (Yi et al., 2022).

Table 1.

A summary of the roles of p300/CBP-mediated protein acetylation in autophagy

A summary of the roles of p300/CBP-mediated protein acetylation in autophagy
A summary of the roles of p300/CBP-mediated protein acetylation in autophagy

The obligatory PIK3C3 complex 1 subunits Beclin 1 (BECN1) and PIK3C3, are regulated by p300-mediated acetylation (Su et al., 2017; Sun et al., 2015) (Fig. 2; Table 1). Of note, both BECN1 and PIK3C3 are acetylated by p300 but not CBP (Su et al., 2017; Sun et al., 2015). Acetylation of BECN1 at K430 and K437 by p300 inactivates PIK3C3 complex 1 by promoting the interaction between BECN1 and rubicon autophagy regulator (RUBCN), which decreases the lipid kinase activity of PIK3C3 (Sun et al., 2015). Acetylation of PIK3C3 at K29, K771 and K781 by p300 also inhibits the complex (Su et al., 2017). Here, acetylation at K29 inhibits complex formation by decreasing the interaction between PIK3C3 and BECN1, whereas acetylation at K771 directly suppresses PtdIns3P synthesis by blocking the affinity of PIK3C3 for its substrate phosphatidylinositol (Su et al., 2017). Therefore, acetylation of BECN1 and PIK3C3 by p300 inhibits the activity of PIK3C3 complex 1 and subsequent initiation of autophagy (Su et al., 2017; Sun et al., 2015).

PIK3C3 forms two distinct heterotetramers, complex 1 and complex 2. BECN1, PIK3C3 and phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4) are the shared components, whereas ATG14L and UV radiation resistance-associated gene protein (UVRAG) are exclusively found in complex 1 and complex 2, respectively (Itakura et al., 2008; Kihara et al., 2001). PIK3C3 complex 1 is critical for autophagy, whereas complex 2 is involved in endocytosis and vacuolar protein sorting (Funderburk et al., 2010). Considering that BECN1 and PIK3C3 are shared by PIK3C3 complex 1 and complex 2, it would be interesting to investigate whether acetylation of BECN1 and PIK3C3 also regulates the activity of PIK3C3 complex 2 and related biological processes, such as endocytosis.

Autophagosome formation

Phagophore growth and expansion is the key event for autophagosome formation, which requires autophagic membrane-bound microtubule associated protein 1 light chain 3 (MAP1LC3 or LC3) and other ATG8 family proteins (Nakatogawa et al., 2007; Nguyen et al., 2016; Xie et al., 2008). In fact, autophagic membrane-bound LC3 (unless otherwise stated, we only use LC3 hereafter to refer to all ATG8 family proteins for simplicity) is also involved in several other autophagy steps, including autophagy initiation, autophagic cargo recruitment and autophagosome–lysosome fusion (Joachim and Tooze, 2016; Kumar et al., 2018; Pankiv et al., 2007).

The lipid phosphatidylethanolamine (PE) is covalently conjugated to LC3 at the C-terminal G120, a site that is exposed by cleavage mediated by the ATG4 proteases (hereafter collectively denoted ATG4) (Kirisako et al., 2000; Tanida et al., 2004) (Fig. 2). With the assistance of two ubiquitylation-like conjugation systems, soluble cleaved LC3 is converted into membrane-bound LC3–PE (Mizushima, 2020) (Fig. 2). First, ATG12 is covalently conjugated to ATG5 by the E1-like enzyme ATG7 and E2-like enzyme ATG10 (Mizushima, 2020). The ATG12–ATG5 conjugate then interacts with ATG16L1 to form the ATG12–ATG5-ATG16L1 complex (Mizushima, 2020), which is recruited to the phagophore by the PtdIns3P-binding protein WD repeat domain phosphoinositide-interacting protein 2 (WIPI2) (Dooley et al., 2014; Polson et al., 2010; Wan and Liu, 2019; Wan et al., 2018). Recently, transmembrane protein stimulator of interferon genes (STING; also known as STING1) has been also reported to mediate WIPI2 recruitment during STING-induced autophagy (Wan and Liu, 2023; Wan et al., 2023). Finally, LC3 is conjugated to PE at the phagophore by the E1-like enzyme ATG7, the E2-like enzyme ATG3 and the ATG12–ATG5-ATG16L1 complex, which acts as an E3 ubiquitin ligase (Mizushima, 2020).

Several proteins from these two ubiquitylation-like conjugation systems are regulated by p300-mediated acetylation (Huang et al., 2015; Lee and Finkel, 2009; Sun et al., 2022) (Fig. 2; Table 1). Acetylation of ATG4 at K39 by p300 but not CBP prevents its interaction with full-length LC3 and so inhibits the subsequent cleavage of LC3, leading to a decrease in LC3–PE formation (Sun et al., 2022). Under nutrient-rich conditions, acetylation of LC3 at K49 and K51 by p300 blocks its interaction with the shuttling protein tumor protein p53-inducible nuclear protein 2 (TP53INP2) and the E1-like enzyme ATG7, which causes the nuclear retention of LC3 and a suppression of LC3 lipidation, resulting in an inhibition of autophagosome formation (Huang et al., 2015; Xu and Wan, 2020; Xu et al., 2016). In addition, acetylation of LC3 has been reported to increase its protein stability by inhibiting its proteasome-dependent degradation, which helps maintain a relatively high level of LC3 in the cell as a reserve for autophagy (Song et al., 2019). Of note, the functions and molecular mechanisms of p300-mediated acetylation of other key components involved in LC3 lipidation, including ATG5, ATG7 and ATG12 (Lee and Finkel, 2009), remain largely unknown and need further investigation.

Autophagosome–lysosome fusion

Autophagosome–lysosome fusion is required for the degradation of autophagic substrates. Soluble N-ethylamide-sensitive factor attachment protein receptor (SNARE) proteins are among the key components that control the fusion between autophagosome and lysosome (Itakura et al., 2012; Jiang et al., 2014; Wang et al., 2016) (Fig. 2). First, the Qa-SNARE protein syntaxin 17 (STX17) is targeted to autophagosome and recruits the Qbc-SNARE synaptosome associated protein 29 (SNAP29) from the cytosol by direct interaction (Itakura et al., 2012). The STX17–SNAP29 subcomplex then interacts with the lysosome-localized R-SNARE vesicle-associated membrane protein 8 (VAMP8) to form the functional SNARE complex, which is required for autophagosome–lysosome fusion (Itakura et al., 2012).

Recently, STX17 has been shown to be acetylated by CBP but not p300 (Shen et al., 2021) (Fig. 2; Table 1). Acetylation of STX17 at K219 and K223 by CBP decreases its interaction with SNAP29 and inhibits the subsequent formation of the STX17–SNAP29–VAMP8 complex, leading to the suppression of autophagosome–lysosome fusion (Shen et al., 2021).

Taken together, p300 and its related protein CBP clearly play pivotal roles in the regulation of autophagy by acetylating a number of factors that function in various autophagy steps. Of note, in addition to the shared substrates, several proteins are selectively acetylated by p300 or CBP. Further study is needed to elucidate the molecular mechanisms underlying the substrate preference of p300 and CBP; this might also provide clues for the functional differences of these two proteins, both in physiological processes and human disorders.

In response to cellular or environmental stimuli, various different mechanisms have been demonstrated to regulate p300 activity and its accessibility to substrates. Here, we summarize the regulation of p300 activity and p300-mediated protein acetylation, and discuss their roles in both physiological and pathophysiological processes, with a focus on autophagy-related events.

Intramolecular inhibition

Structure analysis has revealed that the activity of p300 is controlled by two independent intramolecular inhibition mechanisms (Delvecchio et al., 2013; Thompson et al., 2004) (Fig. 3A,B). The hypoacetylated autoinhibitory loop (AIL) in the C-terminal region binds to an electronegative patch on the histone acetyltransferase (HAT) domain of p300 to complete for binding to substrates (Thompson et al., 2004). p300-mediated autoacetylation of the AIL motif dislodges it from the HAT domain and so abolishes the inhibitory effect of AIL on p300 activity (Thompson et al., 2004). The really interesting new gene (RING) domain at the N-terminal region acts as another intramolecular inhibitor of p300 by steric occlusion of the HAT domain (Delvecchio et al., 2013).

Fig. 3.

Core domain architecture and intramolecular inhibition of p300. (A) Domain structure of human p300. AIL, autoinhibitory loop; Bd, bromodomain; HAT, histone acetyltransferase; PHD, plant homeodomain; RING, really interesting new gene domain. (B) p300 autoinhibition. In its inactive state, the RING domain of p300 occupies the active site located in the HAT domain, and the AIL motif blocks the HAT domain to prevent substrate binding, resulting in the intramolecular inhibition of p300. (C) Regulation of p300 by signaling pathways and small molecules. Distinct protein kinases, such as mTORC1, AMPK, PKB and ERK2, sense different cellular or environmental stimuli, such as amino acids, energy status, tumor necrosis factor (TNF, also known as TNF-α) or epidermal growth factor (EGF) stimulation, to tightly control p300 activity and p300-mediated protein acetylation, resulting in either activation or inhibition of autophagy. In addition, some small molecules, including metabolic intermediate acetyl-CoA and several natural ingredients from food sources as indicated, are involved in autophagy regulation by controlling p300 activity.

Fig. 3.

Core domain architecture and intramolecular inhibition of p300. (A) Domain structure of human p300. AIL, autoinhibitory loop; Bd, bromodomain; HAT, histone acetyltransferase; PHD, plant homeodomain; RING, really interesting new gene domain. (B) p300 autoinhibition. In its inactive state, the RING domain of p300 occupies the active site located in the HAT domain, and the AIL motif blocks the HAT domain to prevent substrate binding, resulting in the intramolecular inhibition of p300. (C) Regulation of p300 by signaling pathways and small molecules. Distinct protein kinases, such as mTORC1, AMPK, PKB and ERK2, sense different cellular or environmental stimuli, such as amino acids, energy status, tumor necrosis factor (TNF, also known as TNF-α) or epidermal growth factor (EGF) stimulation, to tightly control p300 activity and p300-mediated protein acetylation, resulting in either activation or inhibition of autophagy. In addition, some small molecules, including metabolic intermediate acetyl-CoA and several natural ingredients from food sources as indicated, are involved in autophagy regulation by controlling p300 activity.

Cellular signaling pathways

Some disease-related mutations are reported to activate p300 by disrupting the attachment of the RING domain to the HAT domain (Delvecchio et al., 2013). Interestingly, mTORC1 signaling has been reported to be involved in the regulation of p300 activity (Wan et al., 2017) (Fig. 3C). In nutrient-rich conditions, activated mTORC1 phosphorylates p300 at the C-terminal region, which stimulates its activity by preventing the RING domain from interacting with the HAT domain, leading to autophagy inhibition (Wan et al., 2017). This suggests that elimination of RING domain-mediated intramolecular inhibition is also utilized by the cell to activate p300 upon physiological stimuli.

In response to many other intracellular stimuli or environmental cues, such as growth factor stimulation or energy deprivation, various protein kinases, including protein kinase B (PKB, also known as AKT), AMPK and extracellular signal-regulated kinase 2 (ERK2, also known as MAPK1), are activated or inactivated to regulate p300 activity by phosphorylating it at distinct amino acid residues (Chen et al., 2007b; Huang and Chen, 2005; Yang et al., 2001) (Fig. 3C). Several other types of post-translational modifications (PTMs), including sumoylation and methylation, have also been shown to regulate p300 activity (Girdwood et al., 2003; Yadav et al., 2003). However, the roles of these p300-based signaling pathways in autophagy remain elusive. Notably, some of the amino acid residues targeted by the PTMs, including phosphorylation, are located far from the HAT domain of p300. It would be interesting to explore whether these PTMs control p300 activity by affecting the intramolecular inhibition of p300 through the AIL motif or the RING domain.

Interacting partners

Some of the identified interacting partners of p300 have also been demonstrated to affect its activity (Hansson et al., 2009; Miyake et al., 2000; Sen et al., 2008). Mastermind-like protein 1 (MAML1), originally identified as a Notch co-activator, has been reported to interact with the CH3 domain of p300 to potentiate its autoacetylation (Hansson et al., 2009). Interestingly, the AIL motif of p300 is not involved in MAML1-induced autoacetylation and subsequent activation of p300 (Hansson et al., 2009). Whether MAML1–p300 interaction affects the RING domain-dependent intramolecular inhibition of p300 remains unknown and needs further investigation.

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is another interaction partner of p300 that stimulates its activity (Sen et al., 2008). Upon apoptotic stimuli, GADPH undergoes S-nitrosylation in the cytoplasm, which results in the translocation of cytoplasmic GAPDH into the nucleus (Sen et al., 2008). Nuclear GAPDH is then bound and acetylated by p300, which in turn promotes the acetylation of p300 and abolishes its autoinhibition, leading to the activation of p300 (Sen et al., 2008). Nevertheless, how acetylated GAPDH promotes the acetylation of p300 still needs to be elucidated.

In contrast to MAML1 and GAPDH, EP300-interacting inhibitor of differentiation 1 (EID1) has been shown to act as a potent inhibitor of p300 by binding to its CH1 and CH3 domains (Miyake et al., 2000). Upon exiting the cell cycle, EID1 undergoes proteasomal degradation, which abolishes its inhibitory effect on p300, resulting in its activation (Miyake et al., 2000).

Taken together, the interacting partners of p300 are another regulatory mechanism adopted by the cell to control the activity of p300. However, whether they also play key roles in regulating autophagy needs further research.

Subcellular distribution

Given that the substrates of p300 play quite different roles in distinct cellular events, a regulation of the accessibility of p300 to its substrates might provide another layer of tight control over the functions of p300 in the cell. The shuttling protein BAG cochaperone 6 (BAG6, also known as BAT3) has been reported to regulate the accessibility of p300 to its substrates by controlling its subcellular distribution (Sebti et al., 2014). Upon nutrient deprivation, BAG6 promotes the nuclear translocation of cytoplasmic p300, which increases and decreases the accessibility of p300 to the nuclear and cytoplasmic substrates, respectively (Sebti et al., 2014). As a result, the acetylation of the nuclear substrate tumor protein p53 is increased, while the acetylation of its cytoplasmic substrate ATG7 is decreased, leading to upregulation of the transcriptional activity of p53 and activation of autophagy (Sebti et al., 2014).

In summary, it is evident that p300 is regulated by many different mechanisms, including several types of PTMs, change in its interacting partners and redistribution of its subcellular localization, all of which are selectively utilized by the cell to tightly control p300-mediated protein acetylation in various cellular processes, including autophagy, in response to distinct intracellular or extracellular stimuli.

Several metabolic intermediates and natural products have been demonstrated to regulate autophagy by controlling p300 activity. Here, we summarize their roles in p300-regulated autophagy.

Acetyl-CoA

As an important metabolic intermediate, acetyl-CoA plays a key role in the regulation of p300-mediated protein acetylation by providing the acetyl group not only for the acetylation of the substrates but also for the autoacetylation of p300 itself (Thompson et al., 2004). A previous study has shown that manipulation of different metabolic pathways, designed to increase or decrease intracellular acetyl-CoA level, leads to activation or inactivation of p300, respectively (Marino et al., 2014). Functionally, upregulation of cellular acetyl-CoA level causes autophagy inhibition in culture cells and animal model (Marino et al., 2014). Moreover, in vitro acetylation assays in cell-free systems demonstrate that the acetyl-CoA level directly influences the autoacetylation of p300 and its capacity to acetylate the substrates, such as p53 and histone H3 (Marino et al., 2014). These findings suggest that merely manipulating the acetyl-CoA level in the cell is sufficient to control the activity of p300. Of note, most of the autoacetylation sites are located in the AIL motif of p300 (Thompson et al., 2004), indicating that cellular acetyl-CoA might activate p300 by disrupting the AIL motif-dependent intramolecular inhibition.

Natural products

In addition to acetyl-CoA, several small molecules, derived from food sources, have been reported to regulate autophagy by controlling p300 activity (Marcu et al., 2006; Pietrocola et al., 2018, 2015; Xu et al., 2020). Salicylate, the aspirin metabolite, inhibits p300 activity by competing with cellular acetyl-CoA for p300 binding (Pietrocola et al., 2018). Interestingly, several other natural ingredients, such as anacardic acid, curcumin, garcinol and spermidine, have been shown to inhibit p300 activity in vivo and in vitro (Marcu et al., 2006; Pietrocola et al., 2015; Xu et al., 2020). However, the underlying mechanisms, by which these small molecules inhibit p300 activity, remain unclear and need further investigation.

In addition to p300, some of these active ingredients are also known to regulate other key signaling pathways, such as AMPK and mTORC1 signaling in mammalian cells (Din et al., 2012; Hawley et al., 2012; Xu et al., 2020). It would be interesting to investigate whether p300 acts as one of the major upstream effectors for these drugs to regulate the activity of AMPK and mTORC1 in the cell.

Autophagy is a pivotal pathway for the maintenance of cellular homeostasis, and accordingly, dysregulation of autophagy has been linked to the pathogenesis of many human disorders (Fleming et al., 2022; Klionsky et al., 2021; Mizushima and Levine, 2020). Interestingly, alterations of p300, such as gene amplification, nonsense and missense mutations, have also been identified in a number of human diseases, such as cancer and neurodegeneration (Iyer et al., 2004; Kalkhoven, 2004). Notably, many of these mutations are located in the catalytic core, thus resulting in either activation or inactivation of p300 (Delvecchio et al., 2013). Here, we highlight some key examples of p300-regulated autophagy in human disorders, in particular cancer, aging and neurodegeneration.

Cancer

The role of autophagy in cancer appears to be stage dependent. Animal models with deletion of key ATG genes that abolish autophagy have been demonstrated to be prone to tumors (Levy et al., 2017). Similarly, statistical analysis of individuals with primary melanoma suggests that low ATG5 expression levels correlate with accelerated tumor development (Liu et al., 2013). During the cancer initiation stage, autophagy appears to be oncosuppressive (Barthet et al., 2021; Inami et al., 2011; Levy et al., 2017; Liu et al., 2013). However, accumulating evidence supports the notion that autophagy-dependent metabolic reprogramming is required for the increasing metabolic demand of cancer cells during cancer progression (Galluzzi et al., 2015; Kimmelman and White, 2017). For instance, inhibition of autophagy either pharmacologically or genetically makes pancreatic ductal carcinoma more sensitive to ERK inhibitors (Bryant et al., 2019).

Mutations in the RING domain of p300 are linked to Rubinstein–Taybi syndrome (RTS), a developmental disorder with much higher predisposition to cancer, and lead to upregulation of p300 activity (Delvecchio et al., 2013). Considering that activated p300 acts as a potent inhibitor of autophagy, these RTS-linked mutations of p300 might promote cancer initiation by suppressing autophagy. It would be interesting to investigate whether intervention of autophagy has therapeutic potential for cancers that are caused by p300 mutations. Notably, p300 expression has been reported to be significantly reduced in a proportion of breast and colorectal carcinomas (Iyer et al., 2004). Therefore, reduced p300 levels might be responsible for the upregulation of autophagy in cancer cells during cancer progression, but further research is needed to further establish and validate such a link.

Aging

Autophagy has emerged as a key anti-aging pathway across species, evidenced by various studies based on different animal models, including flies, worms and mice (Aman et al., 2021; Wong et al., 2020). The expression of many ATG genes, including ATG5, ATG7 and BECN1, decreases with aging and leads to autophagy inhibition (Lipinski et al., 2010). Decline of autophagy, leading to reduced turnover of proteins and organelles, has recently been suggested to be a hallmark of aging (Lopez-Otin et al., 2023). Indeed, inhibition of autophagy genetically in animal models accelerates aging (Cassidy et al., 2020; Hars et al., 2007), suggesting that the dysfunction of autophagy might be a driving force for the aging process. Intriguingly, stimulation of autophagy genetically is sufficient to increase healthspan and lifespan in animal models (Fernandez et al., 2018; Lu et al., 2021; Pyo et al., 2013). For instance, ubiquitous overexpression of ATG5 in mice causes an increase of basal autophagy, which leads to an improvement of metabolism and an extension of lifespan (Pyo et al., 2013).

p300 has been demonstrated to be the target of several anti-aging drugs, such as nordihydroguairaretic acid and salicylate (Castoldi et al., 2020; Tezil et al., 2019). Interestingly, spermidine, a natural inhibitor of p300, is able to induce autophagy in mice and to extend lifespan by up to 25% (Eisenberg et al., 2016). Of note, the anti-aging effect of spermidine depends on autophagy, evidenced by the loss of the effect on heart with cardiomyocyte-specific knockout of Atg7 in mice (Eisenberg et al., 2016). Considering that spermidine has been demonstrated to induce autophagy by inhibiting p300 activity (Pietrocola et al., 2015), p300 and p300-regulated autophagy might have roles in exerting spermidine-mediated anti-aging effects in mice. However, such a potential link needs to be further verified. In addition to spermidine, there are other natural products that are inhibitors of p300 (Marcu et al., 2006; Pietrocola et al., 2015; Xu et al., 2020), and it would be worthwhile exploring their anti-aging effects in future research efforts.

Neurodegeneration

Most neurodegenerative diseases are characterized by the accumulation of aggregate-prone proteins, such as tau, α-synuclein, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 (TDP-43; also known as TARDBP) (Lee et al., 2011; Ross and Poirier, 2004). A large body of evidence has suggested that these protein aggregates are toxic drivers for the pathogenesis of neurodegeneration (Currais et al., 2017; Lee et al., 2011; Ross and Poirier, 2004; Vaquer-Alicea and Diamond, 2019). Notably, most of these disease-causing protein aggregates can be degraded by the autophagy-lysosome system (Guo et al., 2018; Park et al., 2020). Moreover, mutations of some autophagy-related genes have been identified in several neurodegenerative diseases (Levine and Kroemer, 2019; Nixon, 2013; Yamamoto et al., 2023), suggesting that autophagy dysfunction might cause or promote the accumulation of these toxic protein aggregates. Interestingly, activation of autophagy pharmacologically or genetically is able to enhance the clearance of these protein aggregates and to decrease their toxicities in various model organisms (Lopez et al., 2017; Ravikumar et al., 2004; Sarkar et al., 2007).

It is well established that dysregulation of protein acetylation is highly linked to the pathogenesis of various neurodegenerative diseases (Saha and Pahan, 2006). For instance, in an Alzheimer's disease (AD) model cell line, the expression of p300 is markedly increased (Lu et al., 2014). Moreover, tau acetylation by p300 is an early change in AD brains (Min et al., 2015). Acetylation of tau slows its turnover and induces pathology in mice (Min et al., 2015). Importantly, inhibition of p300 pharmacologically reduces tau levels by stimulating its degradation (Min et al., 2015). Considering that acetylated tau can be degraded by autophagy and microautophagy (Caballero et al., 2021), it would be worthwhile assessing the contribution of p300-regulated autophagy in the clearance of these disease-causing proteins, including tau. In addition, acetylated tau acts as an inhibitor of CMA (Caballero et al., 2021), which is also implicated in the pathogenesis of several neurodegenerative diseases (Wang and Lu, 2022). It thus appears that p300-mediated protein acetylation contributes to the pathogenesis of neurodegenerative diseases through regulating all three types of autophagy pathway.

In addition to cancer, aging and neurodegeneration discussed here, p300-regulated autophagy has also been linked to the pathogenesis of a wide array of human disorders, including metabolic syndromes (Fan et al., 2020; Li et al., 2022). However, more research is needed in the future to systemically investigate the contribution of p300 and p300-regulated autophagy in human disorders.

Although many proteins that function in the autophagy pathway have been identified as targets of p300-mediated acetylation as discussed here, it is nevertheless important to investigate whether other autophagy-related proteins are also acetylated by p300. Here, analysis of the proteome-wide acetylation dynamics during autophagy might help to identify additional targets of p300 and other acetyltransferases systemically.

In addition to bulk autophagy induced by nutrient-sensing pathways, protein acetylation is also involved in the regulation of specific types of autophagy (Xu and Wan, 2023). For instance, acetylation of mitochondrial proteins has been reported to regulate the induction of mitophagy (Webster et al., 2013). Depletion of biogenesis of lysosomal organelles complex 1 subunit 1 (BLOC1S1, also known as GCN5L1), a necessary component of the mitochondrial acetyltransferase machinery, decreases the acetylation of the entire contingent of mitochondrial proteins and promotes the recruitment of autophagy-related proteins to mitochondria, leading to the initiation of mitophagy (Webster et al., 2013). However, the substrates of GCN5L1, which might mediate the recruitment of autophagy machinery remain unknown and need to be identified. In addition, acetylation has been shown to control the delivery of a number of substrates to the lysosome during microautophagy or CMA (Bonhoure et al., 2017; Caballero et al., 2021; Lv et al., 2011). For instance, acetylation of the M2 isoform of pyruvate kinase (PKM2), a key glycolytic enzyme, increases its binding to HSC70, resulting in its lysosomal-dependent degradation via CMA (Lv et al., 2011). However, the role of p300-mediated protein acetylation in the regulation of these processes still needs further investigation. Of note, p300 can be degraded by CMA in cells treated with a chemotherapy drug (Du et al., 2017), suggesting that p300 itself can also be regulated by autophagy-related pathways.

As protein acetylation plays important roles in the regulation of various physiological processes, including autophagy and cell death (Chan and La Thangue, 2001; Menzies et al., 2016; Xu and Wan, 2023), interfering with protein acetylation has emerged as a promising strategy for drug development (Dang and Wei, 2022), and in fact, many deacetylase inhibitors have been approved to treat several types of cancers (Ho et al., 2020). As one of the major acetyltransferases in human cells, p300 is an attractive drug target for human disorders, such as cancer, aging and neurodegeneration. However, owing to the lack of potency or specificity, many p300 inhibitors, including several natural ingredients, are not suitable for drug development (Simon et al., 2016). Recently, several small-molecule inhibitors, targeting the bromodomain and HAT domains of p300, that display high potency and selectivity have been developed (He et al., 2021), providing new hope for p300-based drug development.

The functions and molecular mechanisms underlying protein acetylation have been intensively studied in various cellular processes, and several other types of acylation, including propionylation, butyrylation, succinylation, β-hydroxybutyrylation and lactylation, have emerged as novel PTMs that target lysine residues of proteins (Chen et al., 2007a; Huang et al., 2021; Zhang et al., 2019; Zorro Shahidian et al., 2021). Interestingly, p300 has been demonstrated to be the major acyltransferase that transfers these distinct acyl groups to the substrates (Chen et al., 2007a; Huang et al., 2021; Zhang et al., 2019; Zorro Shahidian et al., 2021). It is therefore worthwhile exploring whether the mechanisms that regulate the activity of p300 as an acetyltransferase are also applicable to its role as an acyltransferase. Considering that these acyl groups are derived from different metabolic intermediates, the local concentration of these metabolic intermediates could determine which type of acyl group is transferred to the lysine residues of the p300 substrates. In this context, it is noteworthy that the same lysine residues of histone H3 can be modified by different acyl groups, with them all mediated by p300 (Chen et al., 2007a; Huang et al., 2021; Zhang et al., 2019; Zorro Shahidian et al., 2021). However, whether these different types of p300-mediated acylations lead to distinct outcomes in cellular processes, such as autophagy, remain largely unknown and need further investigation.

Although p300 has emerged as a master regulator of bulk autophagy, its role in selective autophagy, microautophagy and CMA remains largely unknown. In addition, the link between p300-regulated autophagy and human disorders needs to be verified, which might help in the development on p300-based therapeutic approaches.

Finally, p300 has been shown to catalyze several different types of acylation in cells, whether some established functions of p300 in various different cellular processes, including autophagy, can indeed be attributed to the acetyltransferase activity need to be further validated.

We thank all the members of Dr Wei Wan's lab for constructive comments and helpful discussion.

Funding

Our work in this area was supported by the National Natural Science Foundation of China (31970694), the Science and Technology Innovation Program of Hunan Province (2022RC1171), the Training Program for Excellent Young Innovators of Changsha (kq2206049), the Hunan Provincial Natural Science Foundation of China (2022JJ30186), and the Young Elite Scientists Sponsorship Program by China Association for Science and Technology (CAST) (2019QNRC001).

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Competing interests

The authors declare no competing or financial interests.