bims-nocaut 2025-05-18 papers

Issue of 2025–05–18
five papers selected by
Quentin Frenger, University of Strasbourg

Immunity. 2025 May 09. pii: S1074-7613(25)00186-4. [Epub ahead of print]

Heterozygosity for Crohn's disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection.

Xiaomin Yao, Eugene Rudensky, Patricia K Martin, Brittany M Miller, Isabel Vargas, Erin E Zwack, Keenan A Lacey, Zhengxiang He, Glaucia C Furtado, Sérgio A Lira, Victor J Torres, Bo Shopsin, Ken Cadwell.

The T300A substitution in ATG16L1 associated with Crohn's disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here, we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300A displayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence within the human population.

Keywords: ATG16L1; Crohn’s disease; LC3-associated phagocytosis; Salmonella; autophagy; balancing selection; inflammasome

DOI: https://doi.org/10.1016/j.immuni.2025.04.023

J Cell Physiol. 2025 May;240(5): e70044

Lysosomal Repair in Health and Disease.

Jinrui Xun, Jay Xiaojun Tan.

Lysosomes are essential organelles degrading a wide range of substrates, maintaining cellular homeostasis, and regulating cell growth through nutrient and metabolic signaling. A key vulnerability of lysosomes is their membrane permeabilization (LMP), a process tightly linked to diseases including aging, neurodegeneration, lysosomal storage disorders, and cardiovascular disease. Research progress in the past few years has greatly improved our understanding of lysosomal repair mechanisms. Upon LMP, cells activate multiple membrane remodeling processes to restore lysosomal integrity, such as membrane invagination, tubulation, lipid patching, and membrane stabilization. These repair pathways are critical in preserving cellular stress tolerance and preventing deleterious inflammation and cell death triggered by lysosomal damage. This review focuses on the expanding mechanistic insights of lysosomal repair, highlighting its crucial role in maintaining cellular health and the implications for disease pathogenesis and therapeutic strategies.

Keywords: Atg8ylation; CASM; ESCRT; Lysosomal repair; PITT; annexins; lysosomal membrane permeabilization; microlysophagy; stress granules

DOI: https://doi.org/10.1002/jcp.70044

Microscopy (Oxf). 2025 May 13. pii: dfaf023. [Epub ahead of print]

Discovery of Golgi Membrane-associated Degradation Pathway, GOMED: A Focus on 15 Years of Ultrastructural Analyses.

Satoko Arakawa, Hirofumi Yamaguchi, Shigeomi Shimizu.

In this review, we focus on the ultrastructural characteristics of the Golgi membrane-associated degradation (GOMED) pathway, which have been clarified by electron microscopy and highlight recent advances in the elucidation of its molecular mechanism and physiological roles. The discovery of GOMED, an Atg5/Atg7-independent degradation pathway that differs from canonical autophagy in membrane origin, stimuli, and substrate specificity, has substantially expanded our understanding of intracellular degradation systems. In 2009, we identified GOMED as a novel, evolutionarily conserved autophagic pathway and demonstrated its role in intracellular degradation across eukaryotes, from yeast to mammals. We identified the conserved protein Hsv2/Wipi3 as an essential GOMED protein, which translocates to the trans-Golgi upon induction and remodels Golgi membranes into cup-shaped structures that engulf cytoplasmic components for lysosomal degradation. These processes contribute to organelle and secretory granule turnover, as well as mitochondrial clearance during erythroid differentiation. Moreover, neuronal-specific ablation of Wipi3 in mice causes severe cerebellar degeneration, implicating GOMED in tissue development and homeostasis. As these mechanisms are associated with diseases, such as neurodegenerative disorders and cancer, GOMED mechanisms should also be considered when establishing therapeutic strategies for these diseases.

Keywords: Autophagy; GOMED; Golgi; Mitophagy; Neurodegeneration; Wipi3

DOI: https://doi.org/10.1093/jmicro/dfaf023

Nat Microbiol. 2025 May 15.

ATG5 suppresses type I IFN-dependent neutrophil effector functions during Mycobacterium tuberculosis infection in mice.

Rachel L Kinsella, Chanchal Sur Chowdhury, Asya Smirnov, Yassin Mreyoud, Jacqueline M Kimmey, Ekaterina Esaulova, Samuel R McKee, Aaron Pride, Darren Kreamalmeyer, Maxim N Artyomov, Christina L Stallings.

Inflammation is critical for controlling infections but can cause disease when unchecked. During Mycobacterium tuberculosis (Mtb) infection, neutrophil-dominated inflammation is associated with exacerbated disease. ATG5 expression by neutrophils mediates autophagy-independent control of infection but mechanistic understanding of how this regulates protective neutrophil function is lacking. Using genetic mouse models along with in vivo and in vitro infection systems, we report herein that ATG5 is required in neutrophils to suppress type I interferon-induced PAD4-mediated histone citrullination and neutrophil extracellular trap (NET) release. In addition, ATG5 suppresses type I interferon-induced CXCL2 secretion and neutrophil swarming during Mtb infection. Elevated type I IFN signalling and NET release contribute to the early susceptibility of Atg5fl/fl-LysM-Cre mice during infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during infection, revealing a potential target for host-directed therapies.

DOI: https://doi.org/10.1038/s41564-025-01988-8

J Cell Biol. 2025 Jul 07. pii: e202504129. [Epub ahead of print]224(7):

Atg9 is a conserved regulator of lysosome repair.

Ruoxi Wang, Eric H Baehrecke.

The ATG9 transmembrane protein scrambles lipids to regulate phagophore formation during autophagy. Two recent studies from Peng et al. (https://doi.org/10.1083/jcb.202411092) and De Tito et al. (https://doi.org/10.1101/2024.07.23.604321) identify ATG9 as a conserved regulator of lysosome repair in Caenorhabditis elegans and human cells, but differences in repair mechanisms exist between these taxa.

DOI: https://doi.org/10.1083/jcb.202504129