SMURF2 inhibits autophagic control ofin macrophages.

Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as(Mtb). A key step in this process is the ubiquitination of Mtb or Mtb-associated structures. The E3 ligase SMURF1 catalyzes K48-linked ubiquitination, promoting bacterial clearance. However, the function of its homolog, SMURF2, in host defense remains undefined. Here, we demonstrate thatdeletion in murine macrophages increases SMURF1 levels, enhances LC3B lipidation, augments K48 ubiquitination of Mtb-associated structures, and reduces intracellular Mtb replication. These effects are reversed bydeletion, indicating that SMURF2 restricts autophagy in a SMURF1-dependent manner. Mice with myeloid-specificdeletion exhibit modestly prolonged survival following aerosol Mtb infection. In human macrophages,knockdown or its pharmacological inhibition with the HECT ligase inhibitor Heclin reduces Mtb replication. Together, our findings identify SMURF2 as a negative regulator of selective autophagy and host immunity to Mtb and suggest that targeting SMURF2 may represent a novel host-directed therapeutic strategy for tuberculosis.