期刊
SCIENCE ADVANCES
卷 7, 期 46, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe5469
关键词
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资金
- FONDECYT [3150269, 1180999, 1190203, 1180186, 11180825, 15200002, 1190119, 3210294, 1140522, 3190738, 1190806, PIA ACT192015, P09-015-F]
- ANID/FONDAP program [15150012]
- Millennium Institute [P09-015-F]
- FONDEF [ID16I10223, D11E1007]
- Ecos-Conicyt [C17S02]
- U.S. Air Force Office of Scientific Research [FA9550-16-1-0384]
- U.S. Office of Naval Research-Global (ONR-G) [N62909-16-1-2003]
- Nucleus Physics of Active Matter, FONDEQUIP [EQM130051]
- CONICYT [PCHA/Doctorado Nacional/21120667]
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
- European Research Council (ERC)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- CINV ICM-MINECOM [P09-022-F]
- Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo
- Prof. Dr. Max Cloetta Foundation Medical Research Award
- Swiss National Science Foundation [310030_189094, 310030_189042]
- Academy of Finland FIRI
- U.S. National Institutes of Health [CA231620]
- CONICYT
- FONDAP [15150012]
- Swiss National Science Foundation (SNF) [310030_189042, 310030_189094] Funding Source: Swiss National Science Foundation (SNF)
RECS1, a member of the TMBIM family, acts as a proapoptotic component by inducing cell death through lysosomes. It regulates lysosomal acidification and calcium content, triggering lysosomal membrane permeabilization leading to cell death. Additionally, RECS1 sensitizes whole animals to stress in Drosophila melanogaster and zebrafish models, highlighting its role in apoptosis.
Programmed cell death is regulated by the balance between activating and inhibitory signals. Here, we have identified RECS1 (responsive to centrifugal force and shear stress 1) [also known as TMBIM1 (transmembrane BAX inhibitor motif containing 1)] as a proapoptotic member of the TMBIM family. In contrast to other proteins of the TMBIM family, RECS1 expression induces cell death through the canonical mitochondrial apoptosis pathway. Unbiased screening indicated that RECS1 sensitizes cells to lysosomal perturbations. RECS1 localizes to lysosomes, where it regulates their acidification and calcium content, triggering lysosomal membrane permeabilization. Structural modeling and electrophysiological studies indicated that RECS1 is a pH-regulated calcium channel, an activity that is essential to trigger cell death. RECS1 also sensitizes whole animals to stress in vivo in Drosophila melanogaster and zebrafish models. Our results unveil an unanticipated function for RECS1 as a proapoptotic component of the TMBIM family that ignites cell death programs at lysosomes.
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