Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy

Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li (), Ning Gao () and Xiao-Bo Qiu ()
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Shuo-Shuo Liu: Beijing Normal University
Tian-Xia Jiang: Beijing Normal University
Fan Bu: Beijing Normal University
Ji-Lan Zhao: Beijing Normal University
Guang-Fei Wang: Beijing Normal University
Guo-Heng Yang: Beijing Normal University
Jie-Yan Kong: Beijing Normal University
Yun-Fan Qie: Beijing Normal University
Pei Wen: China Pharmaceutical University
Li-Bin Fan: Anhui Medical University
Ning-Ning Li: Peking University
Ning Gao: Peking University
Xiao-Bo Qiu: Beijing Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Procaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both apoptosis and autophagy by promoting ubiquitylation of proapoptotic factors and the key autophagic protein LC3, respectively. Here we show that BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains, including a ubiquitin-like domain, and the proapoptotic factor Smac/DIABLO binds BIRC6 in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not procaspase 9, for binding BIRC6 in cells. BIRC6 also binds LC3 through its LC3-interacting region, probably following dimer disruption of this BIRC6 region. Mutation at LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Moreover, induction of autophagy promotes autophagic degradation of BIRC6 and caspase 9, but not of other effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

Date: 2024
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DOI: 10.1038/s41467-024-45222-1

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