bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2022–10–30
eleven papers selected by
Quentin Frenger, University of Strasbourg
  1. Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.
  2. Beyond autophagy: LC3-associated phagocytosis and endocytosis.
  3. Many roads lead to CASM: Diverse stimuli of noncanonical autophagy share a unifying molecular mechanism.
  4. LC3-associated endocytosis and the functions of Rubicon and ATG16L1.
  5. Expression and implications of cytology-based miRNAs in oral premalignant and malignant lesions.
  6. LC3-dependent EV loading and secretion (LDELS) promotes TFRC (transferrin receptor) secretion via extracellular vesicles.
  7. Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice.
  8. Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity.
  9. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis.
  10. Neutrophil Nanovesicle Protects against Experimental Autoimmune Encephalomyelitis through Enhancing Myelin Clearance by Microglia.
  11. The Emerging Role of Extracellular Vesicles and Autophagy Machinery in NASH-Future Horizons in NASH Management.
  1. Sci Adv. 2022 Oct 28. 8(43): eabn3298
    Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.
    Yingxue Wang, Maria Ramos, Matthew Jefferson, Weijiao Zhang, Naiara Beraza, Simon Carding, Penny P Powell, James P Stewart, Ulrike Mayer, Thomas Wileman.
      The delivery of pathogens to lysosomes for degradation provides an important defense against infection. Degradation is enhanced when LC3 is conjugated to endosomes and phagosomes containing pathogens to facilitate fusion with lysosomes. In phagocytic cells, TLR signaling and Rubicon activate LC3-associated phagocytosis (LAP) where stabilization of the NADPH oxidase leads to sustained ROS production and raised vacuolar pH. Raised pH triggers the assembly of the vacuolar ATPase on the vacuole membrane where it binds ATG16L1 to recruit the core LC3 conjugation complex (ATG16L1:ATG5-12). This V-ATPase-ATG16L1 axis is also activated in nonphagocytic cells to conjugate LC3 to endosomes containing extracellular microbes. Pathogens provide additional signals for recruitment of LC3 when they raise vacuolar pH with pore-forming toxins and proteins, phospholipases, or specialized secretion systems. Many microbes secrete virulence factors to inhibit ROS production and/or the V-ATPase-ATG16L1 axis to slow LC3 recruitment and avoid degradation in lysosomes.
    DOI:  https://doi.org/10.1126/sciadv.abn3298
  2. Sci Adv. 2022 Oct 28. 8(43): eabn1702
    Beyond autophagy: LC3-associated phagocytosis and endocytosis.
    Carolina Peña-Martinez, Alexis D Rickman, Bradlee L Heckmann.
      Noncanonical functions of the autophagy machinery in pathways including LC3-associated phagocytosis and LC3-associated endocytosis have garnered increasing interest in both normal physiology and pathobiology. New discoveries over the past decade of noncanonical uses of the autophagy machinery in these distinct molecular mechanisms have led to robust investigation into the roles of single-membrane LC3 lipidation. Noncanonical autophagy pathways have now been implicated in the regulation of multiple processes ranging from debris clearance, cellular signaling, and immune regulation and inflammation. Accumulating evidence is demonstrating roles in a variety of disease states including host-pathogen responses, autoimmunity, cancer, and neurological and neurodegenerative pathologies. Here, we broadly summarize the differences in the mechanistic regulation between autophagy and LAP and LANDO and highlight some of the key roles of LAP and LANDO in innate immune function, inflammation, and disease pathology.
    DOI:  https://doi.org/10.1126/sciadv.abn1702
  3. Sci Adv. 2022 Oct 28. 8(43): eabo1274
    Many roads lead to CASM: Diverse stimuli of noncanonical autophagy share a unifying molecular mechanism.
    Joanne Durgan, Oliver Florey.
      Autophagy is a fundamental catabolic process coordinated by a network of autophagy-related (ATG) proteins. These ATG proteins also perform an important parallel role in "noncanonical" autophagy, a lysosome-associated signaling pathway with key functions in immunity, inflammation, cancer, and neurodegeneration. While the noncanonical autophagy pathway shares the common ATG machinery, it bears key mechanistic and functional distinctions, and is characterized by conjugation of ATG8 to single membranes (CASM). Here, we review the diverse, and still expanding, collection of stimuli and processes now known to harness the noncanonical autophagy pathway, including engulfment processes, drug treatments, TRPML1 and STING signaling, viral infection, and other pathogenic factors. We discuss the multiple associated routes to CASM and assess their shared and distinctive molecular features. By integrating these findings, we propose an updated and unifying mechanism for noncanonical autophagy, centered on ATG16L1 and V-ATPase.
    DOI:  https://doi.org/10.1126/sciadv.abo1274
  4. Sci Adv. 2022 Oct 28. 8(43): eabo5600
    LC3-associated endocytosis and the functions of Rubicon and ATG16L1.
    Joëlle Magné, Douglas R Green.
      LC3-associated endocytosis (LANDO) is a noncanonical function of the autophagy machinery, in which LC3 (microtubule-associated protein light chain) is conjugated to rab5-positive endosomes, using a portion of the canonical autophagy pathway. LANDO was initially discovered in a murine model of Alzheimer's disease as a critical regulator of amyloid-β receptor recycling in microglial cells, playing a protective role against neuronal loss and memory impairment. Recent evidence suggests an emerging role of LANDO in cytokine receptor signaling and innate immunity. Here, we discuss the regulation of two crucial effectors of LANDO, Rubicon and ATG16L1, and their impact on endocytosis, autophagy, and phagocytosis.
    DOI:  https://doi.org/10.1126/sciadv.abo5600
  5. Oral Dis. 2022 Oct 27.
    Expression and implications of cytology-based miRNAs in oral premalignant and malignant lesions.
    Xi Yang, Linjun Shi, Guoyao Tang, Zhen Tian, Wei Liu.
      
    Keywords:  Brush biopsy; exfoliated cells; field cancerization; microRNAs; oral cancer; oral potentially malignant disorders
    DOI:  https://doi.org/10.1111/odi.14416
  6. Autophagy. 2022 Oct 26.
    LC3-dependent EV loading and secretion (LDELS) promotes TFRC (transferrin receptor) secretion via extracellular vesicles.
    Jackson O Gardner, Andrew M Leidal, Tan A Nguyen, Jayanta Debnath.
      LC3-dependent EV loading and secretion (LDELS) is a secretory autophagy pathway in which the macroautophagy/autophagy machinery facilitates the packaging of cytosolic cargos, such as RNA-binding proteins, into extracellular vesicles (EVs) for secretion outside of the cell. Here, we identify TFRC (transferrin receptor), one of the first proteins found to be secreted via EVs, as a transmembrane cargo of the LDELS pathway. Similar to other LDELS targets, TFRC secretion via EVs genetically requires components of the MAP1LC3/LC3-conjugation machinery but is independent of other ATGs involved in classical autophagosome formation. Furthermore, the packaging and secretion of this transmembrane protein into EVs depends on multiple ESCRT pathway components and the small GTPase RAB27A. Based on these results, we propose that the LDELS pathway promotes TFRC incorporation into EVs and its secretion outside the cell.
    Keywords:  ATG7; ATG8; LC3-conjugation; extracellular vesicles; secretory autophagy; transferrin receptor
    DOI:  https://doi.org/10.1080/15548627.2022.2140557
  7. Nat Commun. 2022 Oct 24. 13(1): 6233
    Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice.
    Tian Zhou, Yuxin Li, Xiaoyu Li, Fanzhuo Zeng, Yanxia Rao, Yang He, Yafei Wang, Meizhen Liu, Dali Li, Zhen Xu, Xin Zhou, Siling Du, Fugui Niu, Jiyun Peng, Xifan Mei, Sheng-Jian Ji, Yousheng Shu, Wei Lu, Feifan Guo, Tianzhun Wu, Ti-Fei Yuan, Ying Mao, Bo Peng.
      Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-33932-3
  8. Cell Res. 2022 Oct 24.
    Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity.
    Ying Gao, Xueping Zheng, Boyang Chang, Yujie Lin, Xiaodan Huang, Wen Wang, Shirong Ding, Weixiang Zhan, Shang Wang, Beibei Xiao, Lanqing Huo, Youhui Yu, Yilin Chen, Run Gong, Yuanzhong Wu, Ruhua Zhang, Li Zhong, Xin Wang, Qiuyan Chen, Song Gao, Zhengfan Jiang, Denghui Wei, Tiebang Kang.
      STING, an endoplasmic reticulum (ER) transmembrane protein, mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy. Here, we report that activated STING could be transferred between cells to promote antitumor immunity, a process triggered by RAB22A-mediated non-canonical autophagy. Mechanistically, RAB22A engages PI4K2A to generate PI4P that recruits the Atg12-Atg5-Atg16L1 complex, inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome, in which STING activated by agonists or chemoradiotherapy is packaged. This RAB22A-induced autophagosome fuses with RAB22A-positive early endosome, generating a new organelle that we name Rafeesome (RAB22A-mediated non-canonical autophagosome fused with early endosome). Meanwhile, RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome, thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV (RAB22A-induced extracellular vesicle). Activated STING-containing R-EVs induce IFNβ release from recipient cells to the tumor microenvironment, promoting antitumor immunity. Consistently, RAB22A enhances the antitumor effect of the STING agonist diABZI in mice, and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy. Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity, and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV, providing a new perspective for understanding the intercellular communication of organelle membrane proteins.
    DOI:  https://doi.org/10.1038/s41422-022-00731-w
  9. Front Immunol. 2022 ;13 946832
    Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis.
    Jun-Hao Wen, Dong-Yi Li, Shan Liang, Chen Yang, Ji-Xin Tang, Hua-Feng Liu.
      As the essential regulators of organ fibrosis, macrophages undergo marked phenotypic and functional changes after organ injury. These changes in macrophage phenotype and function can result in maladaptive repair, causing chronic inflammation and the development of pathological fibrosis. Autophagy, a highly conserved lysosomal degradation pathway, is one of the major players to maintain the homeostasis of macrophages through clearing protein aggregates, damaged organelles, and invading pathogens. Emerging evidence has shown that macrophage autophagy plays an essential role in macrophage polarization, chronic inflammation, and organ fibrosis. Because of the high heterogeneity of macrophages in different organs, different macrophage types may play different roles in organ fibrosis. Here, we review the current understanding of the function of macrophage autophagy in macrophage polarization, chronic inflammation, and organ fibrosis in different organs, highlight the potential role of macrophage autophagy in the treatment of fibrosis. Finally, the important unresolved issues in this field are briefly discussed. A better understanding of the mechanisms that macrophage autophagy in macrophage polarization, chronic inflammation, and organ fibrosis may contribute to developing novel therapies for chronic inflammatory diseases and organ fibrosis.
    Keywords:  LC3-associated phagocytosis; autophagy; chronic inflammation; fibrosis; macrophage; macrophage polarization
    DOI:  https://doi.org/10.3389/fimmu.2022.946832
  10. ACS Nano. 2022 Oct 26.
    Neutrophil Nanovesicle Protects against Experimental Autoimmune Encephalomyelitis through Enhancing Myelin Clearance by Microglia.
    Shishi Shen, Xi Cheng, Luyao Zhou, Yipeng Zhao, Hai Wang, Jie Zhang, Xiaobo Sun, Yuge Wang, Yaqing Shu, Yanteng Xu, Yu Tao, Mingqiang Li, Zhengqi Lu, Wei Cai, Guangjun Nie, Wei Qiu.
      Timely clearance of myelin debris is the premise of neuroinflammation termination and tissue regeneration in multiple sclerosis (MS). Microglia are the main scavengers of myelin debris in MS lesions, but its phagocytic capability is limited in MS patients. Here, we develop neutrophil-derived nanovesicles (NNVs) to enhance the efficiency of myelin debris clearance in microglia for MS therapy. RNA sequencing (RNAseq) results demonstrate that NNVs treatment ameliorates lesional neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Consequently, EAE mice exhibit favorable neurological functions and white matter integrity after NNVs treatment. Specifically, NNVs treatment upregulates the expression of nuclear factor E2-related factor 2 (NRF2) in microglia, as revealed by Assay for Transposase Accessible Chromatin using sequencing (ATACseq). We also demonstrate that NRF2 can activate the transcription of RUBCN (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein), which in turn enhances LC3-associated phagocytosis (LAP) in microglia. As a result, myelin debris engulfed by microglia can be efficiently catabolized in NNVs-treated EAE mice without obvious side effects. Together, this study proves that NNVs can modulate neuroinflammation by clearing myelin debris and is a promising MS treatment strategy.
    Keywords:  experimental autoimmune encephalomyelitis; microglia; multiple sclerosis; myelin; neutrophil nanovesicles
    DOI:  https://doi.org/10.1021/acsnano.2c07798
  11. Int J Mol Sci. 2022 Oct 12. pii: 12185. [Epub ahead of print]23(20):
    The Emerging Role of Extracellular Vesicles and Autophagy Machinery in NASH-Future Horizons in NASH Management.
    Eleni-Myrto Trifylli, Anastasios G Kriebardis, Evangelos Koustas, Nikolaos Papadopoulos, Melanie Deutsch, Georgios Aloizos, Sotirios P Fortis, Effie G Papageorgiou, Ariadne Tsagarakis, Spilios Manolakopoulos.
      Non-alcoholic fatty liver disease (NAFLD) is considered the most frequent chronic hepatic disease in the general population, while it is the first cause of liver transplantation in the US. NAFLD patients will subsequently develop non-alcoholic steatohepatitis (NASH), which is characterized by aberrant hepatocellular inflammation with or without the presence of fibrosis. The lack of specific biomarkers and therapeutic strategies makes non-alcoholic steatohepatitis (NASH) management a difficult task for clinicians. Extracellular vesicles (EVs) constitute a heterogenic population of vesicles produced by inward or outward plasma-membrane budding. There is an emerging connection between autophagy EVs production, via an unconventional non-degradative procedure. Alterations in the amount of the secreted EVs and the cargo they carry are also involved in the disease progression and development of NASH. Autophagy constitutes a multistep lysosomal degradative pathway that reassures cell homeostasis and survival under stressful conditions, such as oxygen and energy deprivation. It prevents cellular damage by eliminating defected proteins or nοn-functional intracellular organelles. At the same time, it reassures the optimal conditions for the cells via a different mechanism that includes the removal of cargo via the secretion of EVs. Similarly, autophagy machinery is also associated with the pathogenetic mechanism of NAFLD, while it has a significant implication for the progression of the disease and the development of NASH. In this review, we will shed light on the interplay between autophagy and EVs in NASH, the emerging connection of EVs production with the autophagy pathway, and their possible manipulation for developing future therapeutic strategies for NASH.
    Keywords:  autophagy; extracellular vesicles; liver injury; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; steatosis
    DOI:  https://doi.org/10.3390/ijms232012185
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