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*Cell Biology Program, Hospital for Sick Children, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;
Department of Biochemistry, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, and Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway;
Biochemistry Department, Institute of Medical Biology, University of Tromsø, Tromsø, Norway; and
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 J.H.B. holds an Investigators in Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. Infrastructure for the Brumell Laboratory was provided by a New Opportunities Fund from the Canadian Foundation for Innovation and the Ontario Innovation Trust. J.H.B. is a recipient of the Premier’s Research Excellence Award from the Ontario Ministry of Economic Development and Trade and the Boehringer Ingelheim (Canada) Young Investigator Award in Biological Science. Y.T.Z. holds a Restracomp Fellowship from the Hospital for Sick Children. T.J. is supported by grants from the Functional Genomics (FUGE) Program of the Norwegian Research Council, the Norwegian Cancer Society, and the Blix Foundation.
2 Address correspondence and reprint requests to Dr. John H. Brumell, Cell Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail address: john.brumell{at}sickkids.ca
3 Abbreviations used in this paper: EM, electron microscopy; LC3, microtubule-associated protein 1 light chain-3; LIR, LC3 interaction region; MEF, mouse embryonic fibroblast; p.i., postinfection; RFP, red fluorescence protein; SCV, Salmonella-containing vacuole; siRNA, small interfering RNA; SR, small interfering RNA resistant; S. typhimurium, Salmonella enterica serovar Typhimurium; Ub, ubiquitinated protein; UBA, ubiquitin associated.
4 The online version of this article contains supplemental material.
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