Flores-Romero, Hector, Hohorst, Lisa, John, Malina ORCID: 0000-0003-2927-3582, Albert, Marie-Christine, King, Louise E., Beckmann, Laura, Szabo, Tamas, Hertlein, Vanessa, Luo, Xu, Villunger, Andreas ORCID: 0000-0001-8259-4153, Frenzel, Lukas P., Kashkar, Hamid and Garcia-Saez, Ana J. (2022). BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. Embo J., 41 (2). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Flores-Romero, HectorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohorst, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, MalinaUNSPECIFIEDorcid.org/0000-0003-2927-3582UNSPECIFIED
Albert, Marie-ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
King, Louise E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szabo, TamasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertlein, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luo, XuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villunger, AndreasUNSPECIFIEDorcid.org/0000-0001-8259-4153UNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Saez, Ana J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-596719
DOI: 10.15252/embj.2021108690
Journal or Publication Title: Embo J.
Volume: 41
Number: 2
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PORE-FORMING PROTEINS; CYTOCHROME-C RELEASE; BCL-2 FAMILY; CONFORMATIONAL-CHANGES; BH3 DOMAIN; MEMBRANE; BCL-X(L); OLIGOMERIZATION; MITOCHONDRIA; ACTIVATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59671

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