TRIM27 elicits protective immunity against tuberculosis by activating TFEB-mediated autophagy flux.

ABSTRACT

Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of TFEB (transcription factor EB). Specifically, TRIM27 binds to the TFEB promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity toward TFEB, eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.Abbreviations ATG5 autophagy related 5; BMDMs bone marrow-derived macrophages; CFU colony-forming unit; ChIP-seq chromatin immunoprecipitation followed by sequencing; CREB1 cAMP responsive element binding protein 1; CTSB cathepsin B; E3 ubiquitin ligase; EMSA electrophoretic mobility shift assay; HC healthy control; HDT host-directed therapy; LAMP lysosomal associated membrane protein; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MCOLN1 mucolipin TPR cation channel 1; Mtb Mycobacterium tuberculosis; NLS nuclear localization signal; PBMCs peripheral blood mononuclear cells; PRKA/PKA protein kinase cAMP-activated; qRT-PCR quantitative real-time PCR; RFP RET finger protein; TB tuberculosis; TBK1 TANK binding kinase 1; TFEB transcription factor EB; TRIM tripartite motif; TSS transcription start site; ULK1 unc-51 like autophagy activating kinase 1.