Mycobacteria tuberculosis PPE36 modulates host inflammation by promoting E3 ligase Smurf1-mediated MyD88 degradation

Abstract

Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall associated protein is highly specific and conserved for the Mtb complex group. Although it has been proven essential for iron utilization, little is known about the role of PPE36 in regulating host immune responses. Here we exhibited that PPE36 preferentially enriched in Mtb virulent strains, and could efficiently inhibit host inflammatory responses and increase bacterial loads both in mycobacterium-infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (ERK, p38 and JNK) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses, and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation. Author Summary Mycobacterium tuberculosis (Mtb) has developed diverse immune evasion strategies to successfully establish infection in host. Identifying the important Mtb immune regulatory proteins and elucidating the underlying mechanisms are critical for tuberculosis control. Here we demonstrated that PPE36, a Mtb cell-wall associated protein, was predominantly enriched in virulent mycobacterial strains, and obviously inhibited inflammatory responses and facilitated bacterial survival in infected macrophages. Compared with the wild-type BCG, BCG lacking PPE36 (BCGΔPPE36) induced more inflammation, lower bacterial loads as well as the improved histopathological changes in the lungs of infected mice. We further found that PPE36 significantly reduced host MyD88 abundance, and inhibited the activation of subsequunt inflammatory NF-κB and MAPK pathways. In addition, this direct inhibition effect of PPE36 on MyD88 was mediated by the promoted E3 ligase Smurf1 ubiquitin -protesome pathway. This study identified PPE36 as a immune regulatory protein of Mtb, and showed it played an important role in the Mtb immune evasion.