Autophagy serves as a crucial defense mechanism against Mycobacterium tuberculosis (Mtb) survival within infected macrophages. Transcription factor EB (TFEB) and upstream stimulatory factor 2 (USF2) belong to the bHLH-Zip family and regulate the transcription of autophagy-related genes, thereby modulating host-pathogen interactions. However, the mechanisms by which Mtb regulates these transcriptional regulatory factors to inhibit infection remain largely unexplored. This study demonstrated that PE_PGRS23 protein of Mtb impairs macrophage autophagy by inhibiting the transcription of the autophagy gene, thereby enhancing Mtb intracellular survival. Importantly, PE_PGRS23 facilitates the nuclear translocation of TFEB through PI3K-AKT-mTOR-mediated dephosphorylation. Concurrently, PE_PGRS23 promotes the nuclear translocation of USF2, which competes with TFEB for binding to the MAPLC3 promoter, ultimately suppressing MAPLC3 transcription and inhibiting autophagy. Furthermore, murine infection models demonstrated that PE_PGRS23 enhances Mtb survival and exacerbates Mtb-induced lung tissue damage. These findings underscore the critical role of the Mtb PE_PGRS23 protein in inhibiting autophagy by competitively binding of TFEB and USF2 at the MAPLC3 promoter. This mechanism facilitates the intracellular persistence of Mtb, providing theoretical insights into how the pathogen evades innate immune responses.

Keywords: Mycobacterium tuberculosis; Autophagy; PE_PGRS23; TFEB; USF2.