Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins.
Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. However, little is known about mechanisms controlling autophagic degradation of polyubiquitinated proteins. Here, we show that the specific phosphorylation of p62 at serine 403 (S403) in its ubiquitin-associated (UBA) domain increases the affinity between UBA and polyubiquitin chain, resulting in efficiently targeting polyubiquitinated proteins in "sequestosomes" and stabilizing sequestosome structure as a cargo of ubiquitinated proteins for autophagosome entry. Casein kinase 2 (CK2) phosphorylates S403 of p62 directly. Furthermore, CK2 overexpression or phosphatase inhibition reduces the formation of inclusion bodies of the polyglutamine-expanded huntingtin exon1 fragment in a p62-dependent manner. We propose that phosphorylation of p62 at S403 regulates autophagic clearance of ubiquitinated proteins and protein aggregates that are poorly degraded by proteasomes.
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute and CREST/JST, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Gen
G
Matsumoto
Koji
K
Wada
Misako
M
Okuno
Masaru
M
Kurosawa
Nobuyuki
N
Nukina
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D012694:Serine / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D057149:Ubiquitinated Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D057149:Ubiquitinated Proteins; D012694:Serine; D047390:Casein Kinase II; D046988:Proteasome Endopeptidase Complex