Mammalian Atg8 proteins and autophagy factor IRGM control mTOR and TFEB at a regulatory node critical for response to pathogens

Autophagy is a homeostatic process with multiple functions in mammalian cells. Here we show that mammalian Atg8 proteins (mAtg8s) and the autophagy regulator IRGM control TFEB, a transcriptional activator of the lysosomal system. IRGM directly interacted with TFEB and promoted TFEB’s nuclear translocation. An mAtg8 partner of IRGM, GABARAP, interacted with TFEB. Deletion of all mAtg8s or GABARAPs affected global transcriptional response to starvation and down-regulated subsets of TFEB targets. IRGM and GABARAPs countered mTOR’s action as a negative regulator of TFEB. This was suppressed by constitutively active RagB, an activator of mTOR. Infection of macrophages with membrane-permeabilizing microbe Mycobacterium tuberculosis or infection of target cells by HIV elicited TFEB activation in an IRGM-dependent manner. Thus, IRGM and its interactors mAtg8s close a loop between the autophagosomal pathway and the control of lysosomal biogenesis by TFEB ensuring coordinated activation of the two systems that eventually merge during autophagy.