Highlights d A system for membrane repair, removal, and replacement is coordinated by galectins d Galectin-3 recruits ESCRT components to damaged lysosomes to repair them d Galectins induce autophagy to remove damaged lysosomes and activate their biogenesis d The galectin-directed systems protect against M. tuberculosis and neurotoxic tau

The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism-independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of galectin-8 (Gal8) with the mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery, whereas galectin-9 activates AMPK in response to lysosomal injury. Both systems converge upon downstream effectors including autophagy and defense against Mycobacterium tuberculosis. Thus, a novel galectin-based signal-transduction system, termed here GALTOR, intersects with the known regulators of mTOR on the lysosome and controls them in response to lysosomal damage. VIDEO ABSTRACT.

Mammalian autophagosomes mature into autolysosomes through SNARE-driven processes that include syntaxin 17 (Stx17). Kumar et al. show that Stx17 interacts with mammalian Atg8s and with the small guanosine triphosphatase IRGM and that both IRGM and mAtg8s help recruit Stx17 to autophagosomes.

The Ser/Thr protein kinase MTOR (mechanistic target of rapamycin kinase) regulates cellular metabolism and controls macroautophagy/autophagy. Autophagy has both metabolic and quality control functions, including recycling nutrients at times of starvation and removing dysfunctional intracellular organelles. Lysosomal damage is one of the strongest inducers of autophagy, and yet mechanisms of its activation in response to lysosomal membrane damage are not fully understood. Our recent study has uncovered a new signal transduction system based on cytosolic galectins that elicits autophagy by controlling master regulators of metabolism and autophagy, MTOR and AMPK, in response to lysosomal damage. Thus, intracellular galectins are not, as previously thought, passive tags recognizing damage to guide selective autophagy receptors, but control the activation state of AMPK and MTOR in response to endomembrane damage. Abbreviations: MTOR: mechanistic target of rapamycin kinase; AMPK: AMP-activated protein kinase / Protein Kinase AMP-Activated; SLC38A9: Solute Carrier Family 38 Member 9; APEX2: engineered ascorbate peroxidase 2; RRAGA/B: Ras Related GTP Binding A or B; LAMTOR1: Late Endosomal/Lysosomal Adaptor, MAPK and MTOR Activator 1; LGALS8: Lectin, Galactoside-Binding, Soluble, 8 / Galectin 8; LGALS9: Lectin, Galactoside-Binding, Soluble, 9 / Galectin 9; TAK1: TGF-Beta Activated Kinase 1 / Mitogen-Activated Protein Kinase Kinase Kinase 7 (MAP3K7); STK11/LKB1: Serine/Threonine Kinase 11 / Liver Kinase B1; ULK1: Unc-51 Like Autophagy Activating Kinase 1.

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The autophagy pathway known also as macroautophagy (herein referred to as autophagy) is characterized by the formation of double-membrane organelles that capture cytosolic material. Based on pathway termination alternatives, autophagy has been divided into degradative and secretory. During degradative autophagy, autophagosomes typically fuse with lysosomes upon which the sequestered material is degraded. During secretory autophagy, instead of degradation the sequestered cargo is subjected to active secretion or passive release. In this review, we focus on the mechanisms of secretion/passive release of the potent pro-inflammatory cytokine IL-1β, as a prototypical leaderless cytosolic protein cargo studied in the context of secretory autophagy.

Macroautophagy/autophagy plays a role in unconventional secretion of leaderless cytosolic proteins. Whether and how secretory autophagy diverges from conventional degradative autophagy is unclear. We have shown that the prototypical secretory autophagy cargo IL1B/IL-1b (interleukin 1 b) is recognized by TRIM16, and that this first to be identified secretory autophagy receptor interacts with the R-SNARE SEC22B to jointly deliver cargo to the MAP1LC3B-II-positive sequestration membranes. Cargo secretion is unaffected by knockdowns of STX17, a SNARE catalyzing autophagosome-lysosome fusion as a prelude to cargo degradation. Instead, SEC22B in combination with plasma membrane syntaxins completes cargo secretion. Thus, secretory autophagy diverges from degradative autophagy by using specialized receptors and a dedicated SNARE machinery to bypass fusion with lysosomes. The principal morphological feature of autophagy is the formation of a double-membrane organelle called an autophagosome that encloses cytosolic cargo and typically delivers it to lysosomes for degradation. Unconventionally secreted cytosolic proteins are characterized by the absence of leader peptides; thus, they do not enter the lumen of the ER and do not follow the secretory pathway reserved for conventionally secreted proteins that typically go through the ER and the Golgi apparatus, and are secreted by exocytosis of post-Golgi vesicles. An archetypal example of unconventionally secreted proteins is the proinflammatory cytokine IL1B, which has been reported in 1990 as being secreted from mammalian cells despite the absence of a leader peptide. Recently, autophagy as a process has been implicated in the secretion of IL1B in mammalian cells and of the yeast protein Acb1, a homolog of Dictyostelium discoideum AcbA that stimulates encapsulation of prespore cells in the slime mold.Our previous work has shown that IL1B secretion is dependent on autophagy in primary murine bone marrow-derived macrophages. Others have confirmed utilization of the autophagy apparatus for IL1B secretion. How IL1B is recognized for delivery to autophagic organelles en route for secretion and how it is protected from degradation has hitherto remained unknown. Our present work has identified the first specific receptor for secretory autophagy and defined the SNARE apparatus that bypasses autophagosomal maturation but instead leads to secretion of the cargo at the plasma membrane.Diverse lysosome-damaging agents, such as silica, alum, monosodium urate (MSU), and Leu-Leu-O-Me (LLOMe), activate inflammasome, which in turn processes pro-IL1B into mature IL1B, induce autophagy and trigger IL1B secretion. We first established that autophagy factors, e.g. MAP1LC3B and ATG16L1, are required for the efficient secretion of IL1B upon LLOMe treatment. Next, we searched for an IL1B receptor for selective secretory autophagy. The TRIM family proteins (with over 80 members in humans) have been shown to mediate autophagy, act as selective autophagic cargo receptors, and act as organizer...

Autophagy is conventionally described as a degradative, catabolic pathway and a tributary to the lysosomal system where the cytoplasmic material sequestered by autophagosomes gets degraded. However, autophagosomes or autophagosome-related organelles do not always follow this route. It has recently come to light that autophagy can terminate in cytosolic protein secretion or release of sequestered material from the cells, rather than in their degradation. In this review, we address this relatively new but growing aspect of autophagy as a complex pathway, which is far more versatile than originally anticipated.