TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy.
| Title: | TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy. |
|---|---|
| Authors: | Kaur N; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; de la Ballina LR; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.; Haukaas HS; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Torgersen ML; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Radulovic M; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Munson MJ; Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Sabirsh A; Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Stenmark H; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Simonsen A; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.; Carlsson SR; Department of Medical Biochemistry and Biophysics, University of Umeå, Umeå, Sweden.; Lystad AH; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. |
| Source: | The EMBO journal [EMBO J] 2023 Sep 04; Vol. 42 (17), pp. e113105. Date of Electronic Publication: 2023 Jul 06. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2024- : [London] : Nature Publishing Group; Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982- |
| MeSH Terms: | Sphingomyelins* ; Ubiquitins*; Autophagy-Related Protein 5/metabolism ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Autophagy-Related Protein 12/metabolism ; Membrane Proteins/metabolism ; Humans ; Autophagy |
| Abstract: | Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin-like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes to sense membrane damage, but so far, only the mechanism to activate ATG16L1-containing E3 complexes, associated with proton gradient loss, has been described. Here, we show that TECPR1-containing E3 complexes are key mediators of CASM in cells treated with a variety of pharmacological drugs, including clinically relevant nanoparticles, transfection reagents, antihistamines, lysosomotropic compounds, and detergents. Interestingly, TECPR1 retains E3 activity when ATG16L1 CASM activity is obstructed by the Salmonella Typhimurium pathogenicity factor SopF. Mechanistically, TECPR1 is recruited by damage-induced sphingomyelin (SM) exposure using two DysF domains, resulting in its activation and ATG8 lipidation. In vitro assays using purified human TECPR1-ATG5-ATG12 complex show direct activation of its E3 activity by SM, whereas SM has no effect on ATG16L1-ATG5-ATG12. We conclude that TECPR1 is a key activator of CASM downstream of SM exposure.; (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.) |
| Comments: | Comment in: EMBO J. 2023 Oct 4;42(19):e115210. doi: 10.15252/embj.2023115210.. (PMID: 37638605) |
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| Contributed Indexing: | Keywords: CASM; DysF; membrane damage; noncanonical autophagy; sphingomyelin |
| Substance Nomenclature: | 0 (Autophagy-Related Protein 5); 0 (Sphingomyelins); 0 (Autophagy-Related Proteins); 0 (Ubiquitins); 0 (Microtubule-Associated Proteins); 0 (Autophagy-Related Protein 12); 0 (TECPR1 protein, human); 0 (Membrane Proteins) |
| Entry Date(s): | Date Created: 20230706 Date Completed: 20230905 Latest Revision: 20240924 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10476171 |
| DOI: | 10.15252/embj.2022113105 |
| PMID: | 37409525 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't