Regulation of host cell pyroptosis and cytokines production by Mycobacterium tuberculosis effector PPE60 requires LUBAC mediated NF-κB signaling

Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global public health threat. The success of M. tuberculosis largely contributes to its manipulation of host cell fate. The role of M. tuberculosis PE/PPE family effectors in the host destiny was intensively explored. In this study, the role of PPE60 (Rv3478) was characterized by using Rv3478 recombinant M. smegmatis. PPE60 can promote host cell pyroptosis via caspases/NLRP3/gasdermin. The production of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-12p40 and TNF-α was altered by PPE60. We found that LUBAC was involved in PPE60-elicited NF-κB signaling by using Linear Ubiquitin Chain Assembly Complex (LUBAC)–specific inhibitor gliotoxin. The PPE60 recombinant M. smegmatis survival rate within macrophages is increased, as well as elevated resistance to stresses such as low pH, surface stresses and antibiotics exposure. For a first time it is firstly reported that M. tuberculosis effector PPE60 can modulate the host cell fate via LUBAC-mediated NF-κB signaling.