Many cells deal with proteasomal stress by forming micro-aggregates of misfolded ubiquitylated proteins; these are transported along microtubules to the perinuclear region where they assemble into larger aggresomes before being degraded by autophagy. Sequestosome 1 (SQSTM1, also known as p62) has been shown to mediate the self-assembly of misfolded proteins through self-oligomerisation, which facilitates their loading onto dynein motors. However, it is only proteasomal stress and not other stress factors that induces the accumulation of perinuclear aggresomes, suggesting that there is a specific mechanism. Because the p38 mitogen-activated protein kinases (MAPKs) are known stress kinases, Changan Jiang and colleagues (Zhang et al., 2018) systematically investigated the role of the four family members, p38α, p38β, p38γ and p38δ, in aggresome formation and transport. They report that only p38γ and p38δ are required for aggresome formation upon proteasome inhibition with MG132. Moreover, their data show that treatment with MG132 results in p38δ directly interacting with and phosphorylating SQSTM1 at Thr269 and Ser272. These modifications promote aggresome biogenesis, as the use of a phosphomimetic SQSTM1 in p38δ-knockout cells rescued the aggresome formation defect and prevented associated cell death. This work thus reveals p38δ-mediated phosphorylation of SQSTM1 as an important step in the degradation of misfolded protein aggresomes that could also be exploited for the treatment of associated disorders.
Dealing with proteasomal stress: p38δ to the rescue
Dealing with proteasomal stress: p38δ to the rescue. J Cell Sci 15 July 2018; 131 (14): e1404. doi:
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