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ResearchIn-Press PreviewImmunologyInfectious diseaseMicrobiology Open Access | 10.1172/jci.insight.199853

SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages

Priscila C. Campos,1 Kathryn C. Rahlwes,1 Victoria A. Ektnitphong,1 Beatriz R.S. Dias,1 Kubra F. Naqvi,1 Samuel Alvarez-Arguedas,1 and Michael U. Shiloh1

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Rahlwes, K. in: PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Ektnitphong, V. in: PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Dias, B. in: PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Naqvi, K. in: PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Alvarez-Arguedas, S. in: PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Shiloh, M. in: PubMed | Google Scholar

Published September 8, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.199853.
Copyright © 2026, Campos et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 8, 2026 - Version history
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Abstract

Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as Mycobacterium tuberculosis (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 that Smurf2 deletion 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 by Smurf1 deletion, supporting a role for SMURF1 in SMURF2-dependent control of Mtb. Mice with myeloid-specific Smurf2 deletion exhibit modestly prolonged survival following aerosol Mtb infection. In human macrophages, SMURF2 knockdown or its pharmacological inhibition with the HECT E3-ligase inhibitor Heclin reduces Mtb replication. Together, our findings identify SMURF2 as a negative regulator of macrophage control of Mtb and support further investigation of SMURF2 as a potential target for host-directed therapy in tuberculosis.

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