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

Publication date: Available online 22 December 2016
Source:Cell Host & Microbe
Author(s): Luis H. Franco, Vidhya R. Nair, Caitlyn R. Scharn, Ramnik J. Xavier, Jose R. Torrealba, Michael U. Shiloh, Beth Levine
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.

Graphical abstract

Teaser

Franco et al. describe a role for the ubiquitin ligase Smurf1 in selective autophagy of intracellular bacteria including M. tuberculosis (Mtb) and L. monocytogenes. Smurf1 mediates K48 ubiquitination of Mtb and recruitment of the proteasome and autophagy machinery components. Smurf1 helps restrict Mtb replication in macrophages and in mice.


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