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Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy

Cells harness multiple pathways to maintain lysosome integrity, a central homeostatic process. Damaged lysosomes can be repaired or targeted for degradation by lysophagy, a selective autophagy process involving ATG8/LC3. Here, we describe a parallel ATG8/LC3 response to lysosome damage, mechanistica...

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Autores principales: Cross, Jake, Durgan, Joanne, McEwan, David G., Tayler, Matthew, Ryan, Kevin M., Florey, Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561555/
https://www.ncbi.nlm.nih.gov/pubmed/37796195
http://dx.doi.org/10.1083/jcb.202303078
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author Cross, Jake
Durgan, Joanne
McEwan, David G.
Tayler, Matthew
Ryan, Kevin M.
Florey, Oliver
author_facet Cross, Jake
Durgan, Joanne
McEwan, David G.
Tayler, Matthew
Ryan, Kevin M.
Florey, Oliver
author_sort Cross, Jake
collection PubMed
description Cells harness multiple pathways to maintain lysosome integrity, a central homeostatic process. Damaged lysosomes can be repaired or targeted for degradation by lysophagy, a selective autophagy process involving ATG8/LC3. Here, we describe a parallel ATG8/LC3 response to lysosome damage, mechanistically distinct from lysophagy. Using a comprehensive series of biochemical, pharmacological, and genetic approaches, we show that lysosome damage induces non-canonical autophagy and Conjugation of ATG8s to Single Membranes (CASM). Following damage, ATG8s are rapidly and directly conjugated onto lysosome membranes, independently of ATG13/WIPI2, lipidating to PS (and PE), a molecular hallmark of CASM. Lysosome damage drives V-ATPase V0-V1 association, direct recruitment of ATG16L1 via its WD40-domain/K490A, and is sensitive to Salmonella SopF. Lysosome damage-induced CASM is associated with formation of dynamic, LC3A-positive tubules, and promotes robust LC3A engagement with ATG2, a lipid transfer protein central to lysosome repair. Together, our data identify direct ATG8 conjugation as a rapid response to lysosome damage, with important links to lipid transfer and dynamics.
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spelling pubmed-105615552023-10-10 Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy Cross, Jake Durgan, Joanne McEwan, David G. Tayler, Matthew Ryan, Kevin M. Florey, Oliver J Cell Biol Report Cells harness multiple pathways to maintain lysosome integrity, a central homeostatic process. Damaged lysosomes can be repaired or targeted for degradation by lysophagy, a selective autophagy process involving ATG8/LC3. Here, we describe a parallel ATG8/LC3 response to lysosome damage, mechanistically distinct from lysophagy. Using a comprehensive series of biochemical, pharmacological, and genetic approaches, we show that lysosome damage induces non-canonical autophagy and Conjugation of ATG8s to Single Membranes (CASM). Following damage, ATG8s are rapidly and directly conjugated onto lysosome membranes, independently of ATG13/WIPI2, lipidating to PS (and PE), a molecular hallmark of CASM. Lysosome damage drives V-ATPase V0-V1 association, direct recruitment of ATG16L1 via its WD40-domain/K490A, and is sensitive to Salmonella SopF. Lysosome damage-induced CASM is associated with formation of dynamic, LC3A-positive tubules, and promotes robust LC3A engagement with ATG2, a lipid transfer protein central to lysosome repair. Together, our data identify direct ATG8 conjugation as a rapid response to lysosome damage, with important links to lipid transfer and dynamics. Rockefeller University Press 2023-10-05 /pmc/articles/PMC10561555/ /pubmed/37796195 http://dx.doi.org/10.1083/jcb.202303078 Text en © 2023 Cross et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Report
Cross, Jake
Durgan, Joanne
McEwan, David G.
Tayler, Matthew
Ryan, Kevin M.
Florey, Oliver
Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title_full Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title_fullStr Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title_full_unstemmed Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title_short Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy
title_sort lysosome damage triggers direct atg8 conjugation and atg2 engagement via non-canonical autophagy
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561555/
https://www.ncbi.nlm.nih.gov/pubmed/37796195
http://dx.doi.org/10.1083/jcb.202303078
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