The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense

Cell Host Microbe. 2017 Jan 11;21(1):59-72. doi: 10.1016/j.chom.2016.11.002. Epub 2016 Dec 22.

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.

Keywords: K48 ubiquitin; M. tuberculosis; Smurf1; selective autophagy.

MeSH terms

  • Animals
  • Autophagy / immunology*
  • Bacterial Load / physiology
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Listeria monocytogenes / metabolism
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / metabolism
  • Peptides / pharmacology
  • Polyubiquitin / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitination / genetics
  • Ubiquitination / immunology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Lamp1 protein, mouse
  • Lysosome-Associated Membrane Glycoproteins
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Nbr1 protein, mouse
  • Peptides
  • Proteins
  • TAT-BH4 peptide
  • Polyubiquitin
  • Smurf1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex