Open Accessp38δ MAPK regulates aggresome biogenesis by phosphorylating SQSTM1 in response to proteasomal stress
Author(s) -
Chenliang Zhang,
Ju Gao,
Mengen Li,
Yongkang Deng,
Chenfanfu Jiang
Publication year - 2018
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.216671
Subject(s) - biology , aggresome , biogenesis , p38 mitogen activated protein kinases , phosphorylation , microbiology and biotechnology , fight or flight response , mapk/erk pathway , ubiquitin , genetics , gene
Aggresome formation is a major strategy for cells to cope with proteasomal stress. Misfolded proteins are assembled into micro-aggregates and transported to microtubule organization 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 and p38δ, are dispensable for micro-aggregate formation but required for their targeting to MTOC. Interestingly, p38δ promotes micro-aggregate transport through phosphorylating SQSTM1, a major scaffold protein that assembles soluble ubiquitinated 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 MTOC and provides direct evidence for the survival advantages associated with aggresome formation in cells under proteasomal stress.