Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy.
Upon infection of a cell by Salmonella, p62/Sqstm1 assembles on the microbes; simultaneously, p62/Sqstm1 is phosphorylated at Ser351, leading to inactivation of Keap1, which is responsible for degrading Nrf2. Thus, cytoprotective Nrf2 targets are induced at the same time that autophagosomes entrap the microbes (xenophagy). However, the detailed role of p62/Sqstm1 during xenophagy has remained unclear. Here we show that translocation of p62/Sqstm1 to invasive Salmonella precedes Ser351 phosphorylation. Furthermore, in addition to Ser351 phosphorylation, oligomerization of p62/Sqstm1 is also required for localization of Keap1 onto microbes, which is followed by Nrf2 activation. Our data reveal the sequential dynamics of p62/Sqstm1 in response to bacterial infection.
Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Ryosuke
R
Ishimura
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Keiji
K
Tanaka
Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Department of Biochemistry, School of Medicine, Niigata University, Niigata 951-8510, Japan. Electronic address: komatsu-ms@igakuken.or.jp.
Masaaki
M
Komatsu
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000502:physiology*; D054884:Host-Pathogen Interactions; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012480:Salmonella Infections / Q000378:metabolism* / Q000473:pathology; D012486:Salmonella typhimurium / Q000502:physiology*; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin
Autophagy; Keap1; Nrf2; Xenophagy; p62