bims-lypmec 2024-03-24 papers

Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00172-2. [Epub ahead of print]

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Pinki Gahlot, Bojana Kravic, Giulia Rota, Johannes van den Boom, Sophie Levantovsky, Nina Schulze, Elena Maspero, Simona Polo, Christian Behrends, Hemmo Meyer.

Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.

Keywords: ESCRT; ITCH; Troyer syndrome; lipid sensing; lysophagy; lysosomal membrane permeabilization; lysosomal repair; spartin; spastic paraplegia; ubiquitin

DOI: https://doi.org/10.1016/j.molcel.2024.02.029

PLoS Biol. 2024 Mar 22. 22(3): e3002576

One size does not fit all: Lysosomes exist in biochemically and functionally distinct states.

Claudio Bussi, Maximiliano G Gutierrez.

Single-organelle resolution approaches have the potential to advance our knowledge of the heterogeneity of lysosome function. Challenging population-based models, we propose a "lysosome states" concept that links single lysosomes to function.

DOI: https://doi.org/10.1371/journal.pbio.3002576

Autophagy. 2024 Mar 21. 1-2

CASM mediates LRRK2 recruitment and activation under lysosomal stress.

Tomoki Kuwahara, Takeshi Iwatsubo.

Conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments has attracted attention as the non-autophagic function of the Atg8-family protein conjugation system, and the V-ATPase-ATG16L1 axis has emerged as a core mechanism. Our recent research has revealed that this mechanism contributes to the lysosomal recruitment and activation of LRRK2, a Parkinson disease-associated kinase that phosphorylates a subset of RAB GTPases. The activated LRRK2 under CASM-causing lysosomal stress acts to regulate lysosomal morphology and stimulate extracellular secretion of lysosomal contents, thereby promoting the lysosomal stress response.

Keywords: ATG8 conjugation system; CASM; LAP; LRRK2; V-ATPase-ATG16L1 axis; lysosome

DOI: https://doi.org/10.1080/15548627.2024.2330032

Commun Biol. 2024 Mar 15. 7(1): 334

Identification of membrane curvature sensing motifs essential for VPS37A phagophore recruitment and autophagosome closure.

Yansheng Ye, Xinwen Liang, Guifang Wang, Maria C Bewley, Kouta Hamamoto, Xiaoming Liu, John M Flanagan, Hong-Gang Wang, Yoshinori Takahashi, Fang Tian.

VPS37A, an ESCRT-I complex component, is required for recruiting a subset of ESCRT proteins to the phagophore for autophagosome closure. However, the mechanism by which VPS37A is targeted to the phagophore remains obscure. Here, we demonstrate that the VPS37A N-terminal domain exhibits selective interactions with highly curved membranes, mediated by two membrane-interacting motifs within the disordered regions surrounding its Ubiquitin E2 variant-like (UEVL) domain. Site-directed mutations of residues in these motifs disrupt ESCRT-I localization to the phagophore and result in defective phagophore closure and compromised autophagic flux in vivo, highlighting their essential role during autophagy. In conjunction with the UEVL domain, we postulate that these motifs guide a functional assembly of the ESCRT machinery at the highly curved tip of the phagophore for autophagosome closure. These results advance the notion that the distinctive membrane architecture of the cup-shaped phagophore spatially regulates autophagosome biogenesis.

DOI: https://doi.org/10.1038/s42003-024-06026-7