Autophagy controls the quality and quantity of the eukaryotic cytoplasm while performing two evolutionarily highly conserved functions: cell-autonomous provision of energy and nutrients by cytosol autodigestion during starvation, and removal of defunct organelles and large aggregates exceeding the capacity of other cellular degradative systems. In contrast to these autodigestive processes, autophagy in yeast has additional, biogenesis functions. However, no equivalent biosynthetic roles have been described for autophagy in mammals. Here, we show that in mammalian cells, autophagy has a hitherto unappreciated positive contribution to the biogenesis and secretion of the proinflammatory cytokine IL-1b via an export pathway that depends on Atg5, inflammasome, at least one of the two mammalian Golgi reassembly stacking protein (GRASP) paralogues, GRASP55 (GORASP2) and Rab8a. This process, which is a type of unconventional secretion, expands the functional manifestations of autophagy beyond autodigestive and quality control roles in mammals. It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm.

Summary Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key pro-inflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.

IRGM, a human immunity related GTPase, confers autophagic defense against intracellular pathogens by an unknown mechanism. Here we report the unexpected mode of IRGM action. IRGM showed differential affinity for mitochondrial lipid cardiolipin, translocated to mitochondria, affected mitochondrial fission and induced autophagy. Mitochondrial fission was necessary for autophagic control of intracellular mycobacteria by IRGM. IRGM influenced mitochondrial membrane polarization and cell death. Overexpression of IRGMd but not IRGMb splice isoforms caused mitochondrial depolarization and autophagy-independent but Bax/Bak-dependent cell death. By acting on mitochondria IRGM confers autophagic protection or cell death, explaining IRGM action both in defense against tuberculosis and in damaging inflammation in Crohn's disease.

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Autophagy is a major cellular pathway, which at basal levels regulates and maintains the cytoplasmic environment through the capture, isolation and digestion of intracellular materials in a specialized structure called an autophagosome. The unique ability of autophagy to degrade large targets, such as damaged and surplus organelles, intracellular microbes and protein aggregates, has made it a prime focus in inflammation and microbial research. Indeed, autophagy has been shown to be involved in a number of infectious and inflammatory pathologies, by which it may confer protection against intracellular microbes, be targeted by microbes for evasion or be hijacked for microbe biogenesis. In addition, autophagy helps regulate the intracellular and global immune response to both extracellular and intracellular pathogens. Here we review the current literature on the interactions between autophagy and HIV among different immune cells and discuss new research that re-emphasizes the role of inflammation in HIV-mediated CD4 + T cell death. RELEVANT BACKGROUND AND AIM OF THIS REVIEW Autophagy and immunity are fully integrated, and the interface between these processes is slowly emerging and gaining significant attention and traction. The regulation of the innate and adaptive arms of immunity by autophagy occurs partly through the degradative process of autophagy itself, as well as through indirect regulation by autophagy factors and unconventional secretion by the autophagy machinery.