SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages
- 1Department of Internal Medicine and
- 2Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract
Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as Mycobacterium tuberculosis. A key step in this process is the ubiquitination of M. tuberculosis or M. tuberculosis–associated structures. The E3 ligase Smad-specific E3 ubiquitin protein ligase 1 (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 M. tuberculosis–associated structures, and reduces intracellular M. tuberculosis replication. These effects are reversed by Smurf1 deletion, supporting a role for SMURF1 in SMURF2-dependent control of M. tuberculosis. Mice with myeloid-specific Smurf2 deletion exhibit modestly prolonged survival after aerosol M. tuberculosis infection. In human macrophages, SMURF2 knockdown or its pharmacological inhibition with the HECT E3-ligase inhibitor Heclin reduces M. tuberculosis replication. Together, our findings identify SMURF2 as a negative regulator of macrophage control of M. tuberculosis and support further investigation of SMURF2 as a potential target for host-directed therapy in tuberculosis.
Related
- BVL3572S inhibits HisC and AlaA, exploiting vitamin B6 dependency to kill Mycobacterium tuberculosis
- Targeted inhibition of Mycobacterium tuberculosis invasion into macrophages by Rv1768-Rv1983-loaded mannosylated chitosan nanoparticles.
- Defense and subversion: multilevel mitochondrial quality control and pathway‑specific mitophagy outcomes in Mycobacterium tuberculosis infection
- Optimizing diagnosis of Mycobacterium tuberculosis latent infection: ELISpot as a technique of choice for samples with high negative control values in QuantiFERON assay
- Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice
BibTeX
@article{campos2026smurf2,
title = {{SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages}},
author = {Priscila C. Campos and Kathryn C. Rahlwes and Victoria A. Ektnitphong and Beatriz R.S. Dias and Kubra F. Naqvi and Samuel Alvarez-Arguedas and Michael U. Shiloh},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.199853},
url = {https://doi.org/10.1172/jci.insight.199853},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages
AU - Priscila C. Campos
AU - Kathryn C. Rahlwes
AU - Victoria A. Ektnitphong
AU - Beatriz R.S. Dias
AU - Kubra F. Naqvi
AU - Samuel Alvarez-Arguedas
AU - Michael U. Shiloh
PY - 2026
DA - 2026/09/08
JO - JCI Insight
DO - 10.1172/jci.insight.199853
UR - https://doi.org/10.1172/jci.insight.199853
AB - Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as Mycobacterium tuberculosis. A key step in this process is the ubiquitination of M. tuberculosis or M. tuberculosis–associated structures. The E3 ligase Smad-specific E3 ubiquitin protein ligase 1 (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 M. tuberculosis–associated structures, and reduces intracellular M. tuberculosis replication. These effects are reversed by Smurf1 deletion, supporting a role for SMURF1 in SMURF2-dependent control of M. tuberculosis. Mice with myeloid-specific Smurf2 deletion exhibit modestly prolonged survival after aerosol M. tuberculosis infection. In human macrophages, SMURF2 knockdown or its pharmacological inhibition with the HECT E3-ligase inhibitor Heclin reduces M. tuberculosis replication. Together, our findings identify SMURF2 as a negative regulator of macrophage control of M. tuberculosis and support further investigation of SMURF2 as a potential target for host-directed therapy in tuberculosis.
SN - 2379-3708
ER -