TY - JOUR
T1 - BCL-2-family protein tBID can act as a BAX-like effector of apoptosis
AU - Flores-Romero, Hector
AU - Hohorst, Lisa
AU - John, Malina
AU - Albert, Marie Christine
AU - King, Louise E.
AU - Beckmann, Laura
AU - Szabo, Tamas
AU - Hertlein, Vanessa
AU - Luo, Xu
AU - Villunger, Andreas
AU - Frenzel, Lukas P.
AU - Kashkar, Hamid
AU - Garcia-Saez, Ana J.
N1 - Funding Information:
We thank Christian Jüngst, Felix Babatz, Katrin Seidel and Astrid Schauss of the CECAD Imaging Facility, as well as Annika Sarembe, Gudrun Zimmer and Julia Benecke for helpful advice and technical support and Alexandra Kukat and Alexandra Trifunovic for IRES-GFP construct. This project was funded by the Deutsche Forschungsgesellschaft (DFG, German Research foundation), SFB1218, project no. 269925409, and partially SFB1403 – project no. 414786233 and the European Research Council (ERC) (ERC-CoG Grant agreement No. 817758). AV acknowledges support by the Austrian Science Fund, FWF (I-3271) within FOR2036, (New insights into the BCL2 family). L.P.F. received research funding from Hofmann-La Roche and Gilead. L.P.F. obtained consulting and/or speaker’s honoraria and travel support from AbbVie.
Funding Information:
We thank Christian Jüngst, Felix Babatz, Katrin Seidel and Astrid Schauss of the CECAD Imaging Facility, as well as Annika Sarembe, Gudrun Zimmer and Julia Benecke for helpful advice and technical support and Alexandra Kukat and Alexandra Trifunovic for IRES‐GFP construct. This project was funded by the Deutsche Forschungsgesellschaft (DFG, German Research foundation), SFB1218, project no. 269925409, and partially SFB1403 – project no. 414786233 and the European Research Council (ERC) (ERC‐CoG Grant agreement No. 817758). AV acknowledges support by the Austrian Science Fund, FWF (I‐3271) within FOR2036, (New insights into the BCL2 family).
Funding Information:
L.P.F. received research funding from Hofmann‐La Roche and Gilead. L.P.F. obtained consulting and/or speaker’s honoraria and travel support from AbbVie.
Publisher Copyright:
© 2021 The Authors Published under the terms of the CC BY 4.0 license
PY - 2022/12/17
Y1 - 2022/12/17
N2 - 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.
AB - 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.
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U2 - 10.15252/embj.2021108690
DO - 10.15252/embj.2021108690
M3 - Article
C2 - 34931711
AN - SCOPUS:85121451617
SN - 0261-4189
VL - 41
JO - EMBO Journal
JF - EMBO Journal
IS - 2
M1 - e108690
ER -