title: The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense.
abstract: During antibacterial autophagy, ubiquitination of intracellular bacteria recruits proteins that mediate bacterial delivery to the lysosome for degradation. Smurf1 is an E3 ubiquitin ligase whose role in selective bacterial autophagy is unknown. We show that Smurf1 facilitates selective autophagy of the human pathogen Mycobacterium tuberculosis (Mtb). Smurf1-/-macrophages are defective in recruiting polyubiquitin, the proteasome, the ubiquitin-binding autophagy adaptor NBR1, the autophagy protein LC3, and the lysosomal marker LAMP1 to Mtb-associated structures and are more permissive for Mtb growth. This function of Smurf1 requires both its ubiquitin-ligase and C2 phospholipid-binding domains, and involves K48- rather than K63-linked ubiquitination. Chronically infected Smurf1-/-mice have increased bacterial load, increased lung inflammation, and accelerated mortality. SMURF1 controls Mtb replication in human macrophages and associates with bacteria in lungs of patients with pulmonary tuberculosis. Thus, Smurf1 is required for selective autophagy of Mtb and host defense against tuberculosis infection.
authors.affiliation: Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Franco
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Vidhya R
authors.initials: VR
authors.lastname: Nair
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Caitlyn R
authors.initials: CR
authors.lastname: Scharn
authors.affiliation: Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Torrealba
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: michael.shiloh@utsouthwestern.edu.
authors.forename: Michael U
authors.initials: MU
authors.lastname: Shiloh
authors.affiliation: Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: beth.levine@utsouthwestern.edu.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D058491:Bacterial Load / Q000502:physiology; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008089:Listeria monocytogenes / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D010455:Peptides; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D044767:Ubiquitin-Protein Ligases; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C486326:Nbr1 protein, mouse; C540574:TAT-BH4 peptide; C492381:Smurf1 protein, mouse
keywords: K48 ubiquitin; M. tuberculosis; Smurf1; selective autophagy