The heat shock (HS) response is a cellular response to environmental stressors, such as increases in temperature, designed to protect the cell from the impact of these conditions, which could lead to protein misfolding and organelle dysfunction. One such response mechanism involves the nuclear protein lamin A/C (encoded by LMNA), which provides structural integrity to the nucleus. Although lamin A/C has previously been implicated in the nuclear HS response, the underlying mechanisms are unclear. In this study (Virtanen et al., 2023), Pekka Taimen and colleagues demonstrate, both in vitro (in human and mouse cells) and in vivo (in Drosophila), that lamin A/C is phosphorylated at serine 22 in response to HS. This increases lamin A/C nucleoplasmic localisation and consequently the sphericity of the nucleus, whereas unphosphorylated lamin A/C prevents nuclear deformation under HS. Moreover, the authors show that lamina-associated polypeptide 2α (Lap2α), a binding partner of lamin A/C, is downregulated during the HS response. However, this occurs in a lamin A/C-dependent manner, as this reduction in Lap2α is attenuated in lamin A/C knockout cells and LMNA mutant patient fibroblasts. The latter also show impaired cell cycle arrest under HS and compromised survival at recovery. Taken together, these findings demonstrate the importance of lamin A/C and its phosphorylation in the HS response and suggest an evolutionarily conserved mechanism for maintaining nuclear integrity.
