p38δ MAPK regulates aggresome biogenesis by phosphorylating SQSTM1 in response to proteasomal stress.

Aggresome formation is a major strategy to enable cells to cope with proteasomal stress. Misfolded proteins are assembled into micro-aggregates and transported to the microtubule organizing center (MTOC) to form perinuclear aggresomes before their degradation through autophagy. So far, multiple factors have been identified as the activators of micro-aggregate formation, but much less is known about the regulatory mechanisms of their transport. Here, we report that proteasomal stress leads to the activation of p38 MAPK family members. Two of them, p38γ (MAPK12) and p38δ (MAPK13), are dispensable for micro-aggregate formation but are required for their targeting to the MTOC. Interestingly, p38δ promotes micro-aggregate transport by phosphorylating SQSTM1, a major scaffold protein that assembles soluble ubiquitylated proteins into micro-aggregates. Expression of the phospho-mimetic mutant of SQSTM1 in p38δ-knockout cells completely rescued their aggresome formation defects and enhanced their resistance to proteasomal stress to wild-type levels. This study reveals p38δ-mediated SQSTM1 phosphorylation as a critical signal for the targeting of micro-aggregates to the MTOC and provides direct evidence for the survival advantages associated with aggresome formation in cells under proteasomal stress.