The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway.
Autophagy, a cellular degradative pathway, plays a key role in protecting the cytosol from bacterial colonization, but the mechanisms of bacterial recognition by this pathway are unclear. Autophagy is also known to degrade cargo tagged by ubiquitinated proteins, including aggregates of misfolded proteins, and peroxisomes. Autophagy of ubiquitinated cargo requires p62 (also known as SQSTM1), an adaptor protein with multiple protein-protein interaction domains, including a ubiquitin-associated (UBA) domain for ubiquitinated cargo binding and an LC3 interaction region (LIR) for binding the autophagy protein LC3. Previous studies demonstrated that the intracellular bacterial pathogen Salmonella typhimurium is targeted by autophagy during infection of host cells. Here we show that p62 is recruited to S. typhimurium targeted by autophagy, and that the recruitment of p62 is associated with ubiquitinated proteins localized to the bacteria. Expression of p62 is required for efficient autophagy of bacteria, as well as restriction of their intracellular replication. Our studies demonstrate that the surveillance of misfolded proteins and bacteria occurs via a conserved pathway, and they reveal a novel function for p62 in innate immunity.
Zheng
Yiyu T
YT
Cell Biology Program, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Shahnazari
Shahab
S
Brech
Andreas
A
Lamark
Trond
T
Johansen
Terje
T
Brumell
John H
JH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D017510:Protein Folding; D021381:Protein Transport / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000378:metabolism* / Q000472:pathogenicity; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000276:immunology*; D057149:Ubiquitinated Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D057149:Ubiquitinated Proteins