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 the nuclear translocation of TFEB. An mAtg8 partner of IRGM, GABARAP, interacted with TFEB. Deletion of all mAtg8s or GABARAPs affected the global transcriptional response to starvation and downregulated subsets of TFEB targets. IRGM and GABARAPs countered the action of mTOR as a negative regulator of TFEB. This was suppressed by constitutively active RagB, an activator of mTOR. Infection of macrophages with the 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, thus ensuring coordinated activation of the two systems that eventually merge during autophagy.

自噬是哺乳动物细胞中具有多种功能的稳态过程。在这里，我们展示了哺乳动物 Atg8 蛋白 (mAtg8s) 和自噬调节剂 IRGM 控制 TFEB，这是一种溶酶体系统的转录激活剂。IRGM直接与TFEB相互作用，促进TFEB的核转位。IRGM 的 mAtg8 合作伙伴 GABARAP 与 TFEB 进行了交互。删除所有 mAtg8s 或 GABARAPs 会影响对饥饿和下调 TFEB 目标亚群的全球转录反应。IRGM 和 GABARAPs 对抗 mTOR 作为 TFEB 的负调节剂的作用。这被组成型活性 RagB（一种 mTOR 的激活剂）抑制。透膜微生物结核分枝杆菌感染巨噬细胞HIV对靶细胞的感染或感染以IRGM依赖性方式引起TFEB活化。因此，IRGM 及其相互作用物 mAtg8s 在自噬体途径和 TFEB 对溶酶体生物发生的控制之间形成了一个循环，从而确保了在自噬过程中最终合并的两个系统的协调激活。