bims-nocaut 2025-06-08 papers

Issue of 2025–06–08
five papers selected by
Quentin Frenger, University of Strasbourg

Autophagy Rep. 2025 ;4(1): 2476218

The TECPR1:ATG5-ATG12 complex conjugates LC3/ATG8 to damaged lysosomes that expose luminal glycans in response to osmotic imbalance.

Yingxue Wang, Matthew Jefferson, Maria Ramos, Matthew Whelband, Kristin Kreuzer, Grace Khuu, Michael Lazarou, James Mccoll, James Lazenby, Cynthia B Whitchurch, Paul Verkade, Ulrike Mayer, Thomas Wileman.

Hydrolytic enzymes within lysosomes maintain cell and tissue homoeostasis by degrading macromolecules delivered by endocytosis and autophagy. The release of lysosomal enzymes into the cytosol can induce apoptosis and "lysosome-dependent cell death" making it important for damaged lysosomes to be repaired or removed. Extensive lysosome damage exposes luminal sugars to galectin-dependent autophagy pathways that use ATG16L1:ATG5-ATG12 complex to conjugate LC3/ATG8 to autophagosomes to facilitate removal by lysophagy. Sphingomyelin exposed on stressed lysosomes recruits the lysosome tethering protein TECPR1 (tectonin beta propeller repeat-containing protein) allowing an alternative TECRP1:ATG5-ATG12 complex to conjugate LC3 directly to lysosomes. Here we have used cells lacking ATG16L1 to follow the recruitment of TECPR1, galectin-3 and LC3/ATG8 to lysosomes in response to osmotic imbalance induced by chloroquine. TECPR1 was recruited to swollen lysosomes that exposed sphingomyelin. LC3II was absent from swollen lysosomes but located to small puncta that contained the V-ATPase and LAMP1. The presence of galectin-3 and PI4P in the small LC3 puncta suggested that the TECPR1:ATG5-ATG12 complex conjugates LC3 to lysosome remnants that have ruptured in response to osmotic imbalance.

Keywords: ATG16L1; Autophagy; LC3/ATG8; TECPR1; chloroquine; galectin 3; lysosome damage; osmotic stress; sphingomyelin

DOI: https://doi.org/10.1080/27694127.2025.2476218

iScience. 2025 Apr 18. 28(4): 112052

Elimination of intra-hepatocytic malaria parasites is driven by non-canonical autophagy but not nitric oxide production.

Antonino Schepis, Jonas E Mertens, Patrick Lewis, Hardik Patel, Noah Stegman, Laura Reynolds, Nana K Minkah, Stefan H I Kappe.

Elimination of the malaria parasite intra-hepatocytic liver stages (LS) by innate and adaptive immune cells requires interferon gamma (IFN-γ). The current view in the field posits that IFN-γ-mediated elimination of LS is executed by the induction of intra-hepatocytic nitric oxide (NO). Here, we refute this view and instead show that IFN-γ-driven induction of non-canonical autophagy via gamma-aminobutyric acid receptor-associated proteins (GABARAPs) has a critical functional role in IFN-γ-mediated elimination of LS. Furthermore, mediators of lysosomal maturation and fusion also have important functions in this process. Recruitment of GABARAPs to the LS parasitophorous vacuole (PV) compartment likely promotes the fusion of the PV membrane with lysosomes, thereby leading to elimination of intra-hepatocytic parasites. In contrast, LC3 has an infection-supportive function by protecting LS from GABARAP-mediated elimination. We also found an important role of the reactive oxygen species (ROS)-inducing protein NOX2, indicating a two-pronged host response drives LS elimination.

Keywords: Cell biology; Microbiology; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2025.112052

Dev Cell. 2025 May 27. pii: S1534-5807(25)00318-1. [Epub ahead of print]

ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.

Stefano De Tito, Eugenia Almacellas, Daniel Dai Yu, Emily Millard, Wenxin Zhang, Cecilia de Heus, Christophe Queval, Javier H Hervás, Enrica Pellegrino, Ioanna Panagi, Ditte Fogde, Teresa L M Thurston, Judith Klumperman, Maximiliano Gutierrez, Sharon A Tooze.

Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.

Keywords: AP-3; ARFIP2; ATG9A; PI4K2A; PI4P; autophagy; lysosomal damage; lysosome; membrane trafficking

DOI: https://doi.org/10.1016/j.devcel.2025.05.007

Cytokine Growth Factor Rev. 2025 May 22. pii: S1359-6101(25)00051-6. [Epub ahead of print]

The secretion of interleukin-1β.

Susanna G Ford, Patrick Caswell, David Brough, Paula I Seoane.

Interleukin (IL)-1β is a pro-inflammatory cytokine largely produced by cells of the innate immune system in response to tissue damage or to the presence of pathogens. IL-1β-driven inflammation is an established contributor to many disease processes and thus there is great interest in understanding its regulation. This review focusses on the mechanisms involved in the secretion of IL-1β by macrophages. As IL-1β secretion does not follow the conventional ER-Golgi secretory pathway, various mechanisms for IL-1β secretion are proposed, with evidence suggesting that multiple pathways may exist. This review considers the proposed mechanisms determining the secretory pathway of IL-1β.

Keywords: Gasdermin D, Unconventional protein secretion; IL-1β; Inflammation; Pyroptosis

DOI: https://doi.org/10.1016/j.cytogfr.2025.05.005

Sci Adv. 2025 Jun 06. 11(23): eadu9605

HOPS-dependent vesicle tethering lock inhibits endolysosomal fusions and autophagosome secretion upon the loss of Syntaxin17.

Dávid Hargitai, Anikó Nagy, Iván Bodor, Győző Szenci, Hajnalka Laczkó-Dobos, Arindam Bhattacharjee, Natali Neuhauser, Szabolcs Takáts, Gábor Juhász, Péter Lőrincz.

The autophagosomal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein) Syntaxin17 (Syx17) plays a pivotal role in autophagosome-lysosome fusion, yet the broader impact of its loss remains elusive. Our investigation of Syx17 function in Drosophila nephrocytes and salivary gland cells revealed unexpected effects. We find that Syx17 loss induces the formation of autophagosome-lysosome clusters in a HOPS (homotypic fusion and vacuole protein sorting)-dependent manner, entrapping this tether, autophagosomes, and lysosomes. While locked in clusters, these organelles cannot participate in other vesicle fusions, impeding endosomal progression and autophagosome secretion. Therefore, the absence of Syx17 not only inhibits autophagosome-lysosome fusion but also prevents HOPS release from autophagosome-lysosome tethering sites causing a "tethering lock." Preventing autophagosome formation or removing the HOPS adaptor Plekhm1 (pleckstrin homology domain-containing family M member 1) leads to release of HOPS and lysosomes from these clusters, thus rescuing secondary effects of Syx17 loss. Our findings show that a tethering lock can disrupt multiple vesicle trafficking routes.

DOI: https://doi.org/10.1126/sciadv.adu9605