Blocking USP15 boosts immunity against tuberculosis

Tuberculosis remains a major global health threat because the bacterium Mycobacterium tuberculosis (Mtb) can live inside immune cells called macrophages. One way macrophages fight these hidden bacteria is with autophagy, a process that packages and sends bacterial material to cellular recycling centers called lysosomes. Previous work showed that enzymes called E3 ubiquitin ligases — including PARKIN and SMURF1 — mark Mtb-associated material with ubiquitin, flagging it for autophagy. But ubiquitin marks can be removed by enzymes known as deubiquitinases (DUBs), and researchers led by corresponding author Michael U. Shiloh asked whether any DUBs might be dampening the macrophage response to Mtb. To test this idea, the team performed a focused genetic screen in mouse macrophages to look for DUBs that limit the ubiquitin-driven pathway. Their screen pointed to ubiquitin-specific protease 15 (USP15) as a candidate negative regulator of autophagy-based defense against Mtb. The discovery set up follow-up experiments to determine how USP15 affects ubiquitin tagging, autophagy machinery, and bacterial survival inside host cells.

The investigators used a targeted knockdown screen in mouse macrophages to probe the role of USP15. When they reduced Usp15 expression, they observed more K63-linked ubiquitination on Mtb-associated structures and increased recruitment of the autophagy protein LC3, changes that were associated with reduced bacterial replication. These effects depended on USP15’s catalytic activity: the dampening of autophagy required an active enzyme. The team also showed that knocking down PARKIN (Park2) or blocking autophagy initiation reversed the benefits seen after Usp15 loss, indicating that USP15 acts by countering ubiquitin ligase–driven tagging that leads to LC3 recruitment. Extending the findings to human cells, USP15 knockdown in primary human macrophages likewise enhanced LC3 targeting of Mtb and restricted bacterial growth. Importantly for potential therapies, pharmacologic inhibition of USP15 with a selective small molecule also decreased Mtb burden in human macrophages, showing that both genetic and chemical approaches to reduce USP15 activity can boost this host defense pathway.

These results identify USP15 as a suppressor of macrophage immunity against Mtb and point to deubiquitinases as potential targets for host-directed therapies. By removing ubiquitin marks that would otherwise recruit autophagy machinery, USP15 limits the cell’s ability to deliver Mtb to lysosomes; reducing USP15 activity restores those marks, increases LC3 recruitment, and lowers bacterial replication in cultured macrophages. The fact that a selective small molecule inhibitor of USP15 mirrored the effects of genetic knockdown in primary human macrophages is especially suggestive: it raises the possibility of developing drugs that boost a person’s own immune cells to fight tuberculosis. Translating this idea into treatments will require further work to test safety, dosing, and effectiveness in animal models and clinical studies, and to understand how USP15 inhibition interacts with existing antibiotic regimens. Still, targeting DUBs such as USP15 offers a new angle on strengthening cellular defenses against a pathogen that survives inside immune cells.