Mycobacterium tuberculosis (Mtb) employs a multifaceted arsenal to elude host defense mechanisms, including those associated with autophagy and lysosome function. Within the realm of host-pathogen interactions, NCOR1, a well-recognized transcriptional co-repressor, is known to associate with a multitude of protein complexes to effect the repression of a diverse spectrum of genes. However, its role in regulating macroautophagy/autophagy, lysosome biogenesis, and, by extension, Mtb pathogenesis remains unexplored. The depletion of NCOR1 assumes a pivotal role in the control of the AMPK-MTOR-TFEB signaling axis, thereby fine-tuning cellular ATP homeostasis. This finely orchestrated adjustment further alters the profile of proteins involved in autophagy and lysosomal biogenesis through its master regulator, TFEB, culminating in the increased Mtb survival within the host milieu. Furthermore, the treatment of NCOR1-depleted cells with either rapamycin, antimycin A, or metformin demonstrates a capacity to restore the TFEB activity and LC3-II levels, consequently restoring the capacity of host cells to clear Mtb. Additionally, exogenous NCOR1 expression rescues the AMPK-MTOR-TFEB signaling axis and essentially the autophagic induction machinery. Overall, these findings demonstrate a crucial role of NCOR1 in regulating Mtb pathogenesis within myeloid cells and sheds light toward its involvement in the development of novel host-directed therapies.
Keywords: AMPK; MTOR; NCOR1; TFEB; mycobacterium tuberculosis.