TRIM27 mediates protective immunity against tuberculosis by activating host autophagy flux

Infectious diseases remain a major global health threat exacerbated by emerging drug resistance. Host-directed therapy (HDT) is a complementing strategy for infectious disease treatment through targeting host immune mechanisms. However, the poorly understood host factors modulating infectious disease including tuberculosis (TB), a Mycobacterium tuberculosis (Mtb)-caused chronic infection with severe drug resistance, has impeded HDT development. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) mediates host protective immunity in TB independent of its E3 activity. Mechanistically, TRIM27 enters host cell nucleus upon Mtb infection, and interacts with cAMP responsive element binding protein 1 (CREB1) to form a transcription factor complex to promote transcription factor EB (TFEB) transcription through enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 phosphorylation, eventually leading to autophagy-related gene expression and autophagy-mediated Mtb clearance. Thus, our findings reveal that TRIM27 contributes to host anti-Mtb immunity, indicating a promising HDT-based TB treatment via targeting TRIM27/CREB1-TFEB axis.