Sorting nexin 5 mediates virus-induced autophagy and immunity.

Autor: Dong X; Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA., Yang Y; Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zou Z; Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhao Y; Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ci B; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhong L; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Bhave M; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Wang L; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Kuo YC; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zang X; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhong R; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Aguilera ER; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Richardson RB; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Simonetti B; School of Biochemistry, University of Bristol, Bristol, UK., Schoggins JW; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Pfeiffer JK; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Yu L; The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China., Zhang X; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Xie Y; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Schmid SL; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Xiao G; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Gleeson PA; Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, Australia.; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia., Ktistakis NT; Signalling Programme, The Babraham Institute, Cambridge, UK., Cullen PJ; School of Biochemistry, University of Bristol, Bristol, UK., Xavier RJ; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.; Broad Institute of MIT and Harvard University, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu., Levine B; Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Jan; Vol. 589 (7842), pp. 456-461. Date of Electronic Publication: 2020 Dec 16.
DOI: 10.1038/s41586-020-03056-z
Abstrakt: Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases 1,2 . Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5) 3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism-SNX5-dependent PI3KC3-C1 activation at endosomes-for initiation of autophagy during viral infection.
Databáze: MEDLINE
Externí odkaz: