bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–04–13
eight papers selected by
Quentin Frenger, University of Strasbourg
  1. RAB5c controls the assembly of non-canonical autophagy machinery to promote phagosome maturation and microbicidal function of macrophages.
  2. Lysosome-associated CASM: from upstream triggers to downstream effector mechanisms.
  3. Autophagy machinery as exploited by viruses.
  4. The autophagy protein ATG-9 regulates lysosome function and integrity.
  5. STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
  6. An unconventional autophagic pathway that inhibits ATP secretion during apoptotic cell death.
  7. TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
  8. The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.
  1. bioRxiv. 2025 Mar 28. pii: 2025.03.25.645097. [Epub ahead of print]
    RAB5c controls the assembly of non-canonical autophagy machinery to promote phagosome maturation and microbicidal function of macrophages.
    Edismauro Garcia Freitas-Filho, Isabella Zaidan, Marlon Fortes-Rocha, Daniel Leonardo Alzamora-Terrel, Carolina Bifano, Patrícia Alves de Castro, Renan Eugênio Araujo Piraine, Camila Figueiredo Pinzan, Caroline Patine de Rezende, Emilio Boada-Romero, Fausto Bruno Dos Reis Almeida, Gustavo Henrique Goldman, Oliver Florey, Larissa Dias Cunha.
      Non-canonical conjugation of ATG8 proteins, including LC3, to single membranes implicates the autophagy machinery in cell functions unrelated to metabolic stress. One such pathway is LC3-associated phagocytosis (LAP), which aids in phagosome maturation and subsequent signaling upon cargo uptake mediated by certain innate immunity-associated receptors. Here, we show that a specific isoform of RAB5 GTPases, the molecular switches controlling early endosome traffic, is necessary for LAP. We demonstrate that RAB5c regulates phagosome recruitment and function of complexes required for phosphatidylinositol-3-phosphate [PI(3)P] and reactive oxygen species (ROS) generation by macrophages. RAB5c facilitates phagosome translocation of the V-ATPase transmembrane core, which is needed for ATG16L1 binding and consequent LC3 conjugation. RAB5c depletion impaired macrophage elimination of the fungal pathogen Aspergillus fumigatus and disruption of the V-ATPase-ATG16L1 axis increased susceptibility in vivo . Therefore, early endosome-to-phagosome traffic is differentially regulated to promote LAP and ROS contributes to resistance against A. fumigatus by effecting LAP.
    HIGHLIGHTS: RAB5c is required for LC3-associated phagocytosisRAB5c finetunes NAPDH oxidase assembly and ROS generation in the phagosomeRAB5c regulates V-ATPase assembly on the phagosome RAB5c and V-ATPase-ATG16L1 axis are required for the killing of A. fumigatus.
    DOI:  https://doi.org/10.1101/2025.03.25.645097
  2. Front Cell Dev Biol. 2025 ;13 1559125
    Lysosome-associated CASM: from upstream triggers to downstream effector mechanisms.
    Namrita Kaur, Sven R Carlsson, Alf Håkon Lystad.
      Lysosomes are dynamic organelles critical for cellular degradation and signaling, safeguarded by a limiting membrane that prevents leakage of harmful contents into the cytoplasm. Upon lysosomal damage, cells deploy defensive mechanisms, including a key process called CASM (conjugation of ATG8 to single membranes), which lipidates ATG8 proteins onto the limiting membrane to support protective pathways. CASM operates through two pathways: VAIL, induced by lysosomal pH changes via V-ATPase and ATG16L1, and STIL, triggered by sphingomyelin exposure and mediated by TECPR1. This review examines CASM's role in lysosomal damage responses, exploring the mechanisms of damaging agents, distinctions between VAIL and STIL, and the downstream effects of decorating lysosomes with ATG8, including effector recruitment for membrane repair or removal.
    Keywords:  Atg8; CASM; STIL; VAIL; atg8ylation; autophagy; lysosome damage
    DOI:  https://doi.org/10.3389/fcell.2025.1559125
  3. Autophagy Rep. 2025 Dec 31. pii: 27694127.2025.2464986. [Epub ahead of print]4(1):
    Autophagy machinery as exploited by viruses.
    Christian Münz, Grant R Campbell, Audrey Esclatine, Mathias Faure, Patrick Labonte, Marion Lussignol, Anthony Orvedahl, Nihal Altan-Bonnet, Ralf Bartenschlager, Rupert Beale, Mara Cirone, Lucile Espert, Jae Jung, David Leib, Fulvio Reggiori, Sumana Sanyal, Stephen A Spector, Volker Thiel, Christophe Viret, Yu Wei, Thomas Wileman, Harald Wodrich.
      Viruses adapt and modulate cellular pathways to allow their replication in host cells. The catabolic pathway of macroautophagy, for simplicity referred to as autophagy, is no exception. In this review, we discuss anti-viral functions of both autophagy and select components of the autophagy machinery, and how viruses have evaded them. Some viruses use the membrane remodeling ability of the autophagy machinery to build their replication compartments in the cytosol or efficiently egress from cells in a non-lytic fashion. Some of the autophagy machinery components and their remodeled membranes can even be found in viral particles as envelopes or single membranes around virus packages that protect them during spreading and transmission. Therefore, studies on autophagy regulation by viral infections can reveal functions of the autophagy machinery beyond lysosomal degradation of cytosolic constituents. Furthermore, they can also pinpoint molecular interactions with which the autophagy machinery can most efficiently be manipulated, and this may be relevant to develop effective disease treatments based on autophagy modulation.
    Keywords:  Endosomal damage; interferon; replication organelle; secretory autophagy; virophagy
    DOI:  https://doi.org/10.1080/27694127.2025.2464986
  4. J Cell Biol. 2025 Jun 02. pii: e202411092. [Epub ahead of print]224(6):
    The autophagy protein ATG-9 regulates lysosome function and integrity.
    Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N Noda, Hong Zhang.
      The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.
    DOI:  https://doi.org/10.1083/jcb.202411092
  5. Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]
    STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
    Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.
      Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.
    Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
  6. Nat Commun. 2025 Apr 10. 16(1): 3409
    An unconventional autophagic pathway that inhibits ATP secretion during apoptotic cell death.
    Elena Terraza-Silvestre, Raquel Villamuera, Julia Bandera-Linero, Michal Letek, Daniel Oña-Sánchez, Cristina Ramón-Barros, Clara Moyano-Jimeno, Felipe X Pimentel-Muiños.
      Mobilisation of Damage-Associated Molecular Patterns (DAMPs) determines the immunogenic properties of apoptosis, but the mechanisms that control DAMP exposure are still unclear. Here we describe an unconventional autophagic pathway that inhibits the release of ATP, a critical DAMP in immunogenic apoptosis, from dying cells. Mitochondrial BAK activated by BH3-only molecules interacts with prohibitins and stomatin-1 through its latch domain, indicating the existence of an interactome specifically assembled by unfolded BAK. This complex engages the WD40 domain of the autophagic effector ATG16L1 to induce unconventional autophagy, and the resulting LC3-positive vesicles contain ATP. Functional interference with the pathway increases ATP release during cell death, reduces ATP levels remaining in the apoptotic bodies, and improves phagocyte activation. These results reveal that an unconventional component of the autophagic burst that often accompanies apoptosis sequesters intracellular ATP to prevent its release, thus favouring the immunosilent nature of apoptotic cell death.
    DOI:  https://doi.org/10.1038/s41467-025-58619-3
  7. Autophagy. 2025 Apr 07.
    TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
    Pablo J Tapia, José A Martina, Pablo S Contreras, Akriti Prashar, Eutteum Jeong, Dominic De Nardo, Rosa Puertollano.
      STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB- and TFE3-depleted iBMDMs. Conversely, TFEB overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.
    Keywords:  Autophagy; STING1; TFE3; TFEB; immune response; lysosomes
    DOI:  https://doi.org/10.1080/15548627.2025.2487036
  8. Nat Cell Biol. 2025 Apr 10.
    The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.
    Xinbo Wang, Peng Xu, Amanda Bentley-DeSousa, William Hancock-Cerutti, Shujun Cai, Benjamin T Johnson, Francesca Tonelli, Lin Shao, Gabriel Talaia, Dario R Alessi, Shawn M Ferguson, Pietro De Camilli.
      Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.
    DOI:  https://doi.org/10.1038/s41556-025-01653-6
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒22 at 6:04.