bims-nocaut 2025-02-23 papers

Issue of 2025–02–23
five papers selected by
Quentin Frenger, University of Strasbourg

Proc Natl Acad Sci U S A. 2025 Feb 25. 122(8): e2415422122

STING-induced noncanonical autophagy regulates endolysosomal homeostasis.

Tuozhi Huang, Chenglong Sun, Fenghe Du, Zhijian J Chen.

The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH-elevated Golgi-derived vesicles that led to ATG16L1 and V-ATPase-dependent noncanonical autophagy. We showed that STING-induced noncanonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin-interacting proteins (FNIPs), thereby sequestering the FNIP-folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING-induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease, through GABARAPs lipidation. We further showed that STING-induced autophagy induced ALIX-mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING-induced noncanonical autophagy in regulating endolysosomal homeostasis.

Keywords: ESCRT; STING; TFEB; autophagy; cGAS

DOI: https://doi.org/10.1073/pnas.2415422122

Curr Opin Cell Biol. 2025 Feb 20. pii: S0955-0674(25)00020-1. [Epub ahead of print]93 102482

LRRK2, lysosome damage, and Parkinson's disease.

Amanda Bentley-DeSousa, Devin Clegg, Shawn M Ferguson.

Limited understanding of regulatory mechanisms controlling LRRK2 kinase activity has hindered insights into both its normal biology and how its dysregulation contributes to Parkinson's disease. Fortunately, recent years have yielded an increased understanding of how LRRK2 kinase activity is dynamically regulated by recruitment to endolysosomal membranes. Notably, multiple small GTPases from the Rab family act as both activators and substrates of LRRK2. Additionally, it was recently discovered that LRRK2 is recruited to, and activated at, stressed or damaged lysosomes through an interaction with GABARAP via the CASM (conjugation of ATG8 to single membranes) pathway. These discoveries position LRRK2 within the rapidly growing field of lysosomal damage and repair mechanisms, offering important insights into lysosome biology and the pathogenesis of Parkinson's disease.

DOI: https://doi.org/10.1016/j.ceb.2025.102482

Mol Biol Cell. 2025 Feb 19. mbcE24120535

Trafficking of K63-polyubiquitin modified membrane proteins in a macroautophagy-independent pathway is linked to ATG9A.

Francesco Scavone, Sharon Lian, Eeva-Liisa Eskelinen, Robert E Cohen, Tingting Yao.

Cytoplasmic K63-linked polyubiquitin signals have well-established roles in endocytosis and selective autophagy. However, how these signals help to direct different cargos to different intracellular trafficking routes is unclear. Here we report that, when the K63-polyubiquitin signal is blocked by intracellular expression of a high-affinity sensor (named Vx3), many proteins originating from the plasma membrane are found trapped in clusters of small vesicles that co-localize with ATG9A, a transmembrane protein that plays an essential role in autophagy. Importantly, whereas ATG9A is required for cluster formation, other core autophagy machinery as well as selective autophagy cargo receptors are not required. Although the cargos are sequestered in the vesicular clusters in an ATG9-dependent manner, additional signals are needed to induce LC3 conjugation. Upon removal of the Vx3 block, K63-polyubiquitylated cargos are rapidly delivered to lysosomes. These observations suggest that ATG9A plays an unexpected role in the trafficking of K63-polyubiquitin modified membrane proteins. [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E24-12-0535

Autophagy. 2025 Feb 19.

Lysosomal Quality Control.

Danielle Henn, Xi Yang, Ming Li.

Healthy cells need functional lysosomes to degrade cargo delivered by autophagy and endocytosis. Defective lysosomes can lead to severe conditions such as lysosomal storage diseases (LSDs) and neurodegeneration. To maintain lysosome integrity and functionality, cells have evolved multiple quality control pathways corresponding to different types of stress and damage. These can be divided into five levels: regulation, reformation, repair, removal, and replacement. The different levels of lysosome quality control often work together to maintain the integrity of the lysosomal network. This review summarizes the different quality control pathways and discusses the less-studied area of lysosome membrane protein regulation and degradation, highlighting key unanswered questions in the field.

Keywords: ESCRT; Lysophagy; lysosome membrane protein regulation; lysosome membrane repair; lysosome quality control

DOI: https://doi.org/10.1080/15548627.2025.2469206

Autophagy. 2025 Feb 20.

Physiological Insights into ESCRT-Mediated Phagophore Closure: Potential Cytoprotective Roles for ATG8ylated Membranes.

Kouta Hamamoto, Xinwen Liang, David M Opozda, Hong-Gang Wang, Yoshinori Takahashi.

The endosomal sorting complex required for transport (ESCRT) machinery is a membrane abscission system that mediates various intracellular membrane remodeling processes, including macroautophagy/autophagy. In our recent study, we established the unique requirement of the ubiquitin E2 variant-like (UEVL) domain of the ESCRT-I subunit VPS37A in phagophore closure, the final step in autophagosome biogenesis, and determined the physiological impact of systemically inhibiting closure by targeting this region in mice. While the mutant mice exhibited phenotypes similar to those reported in mice deficient in generating ATG8 (mammalian Atg8 homologs)-conjugated (ATG8ylated) phagophores, certain phenotypes, such as neonatal lethality and liver injury, were found to be notably milder. Further investigation revealed that ATG8ylated phagophores promote TBK1-dependent SQSTM1 phosphorylation and droplet formation, leading to the formation of large insoluble aggregates upon closure inhibition. These findings suggest potential roles for ATG8ylated membranes in mitigating proteotoxicity by efficiently concentrating and sequestering soluble, reactive microaggregates and converting them into less reactive, insoluble large aggregates. The study highlights VPS37A UEVL mutant mice as a model for investigating the physiological and pathological roles of phagophores that extend beyond degradation.

Keywords: ATG8ylation; ESCRT; SQSTM1; TBK1; VPS37A UEVL mutant mouse; phagophore closure

DOI: https://doi.org/10.1080/15548627.2025.2468907