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Article Dans Une Revue Nature Structural and Molecular Biology Année : 2023

Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2

Adam Tencer
  • Fonction : Auteur
Yucong Yu
  • Fonction : Auteur
Sebastien Causse
  • Fonction : Auteur
Grant Campbell
Brianna Klein
Hongwen Xuan
  • Fonction : Auteur
Jessy Cartier
  • Fonction : Auteur
Mark Miles
Nitika Gaurav
  • Fonction : Auteur
Aymeric Zadoroznyj
  • Fonction : Auteur
Tina Holt
Hong Wen
Christine Hawkins
Stephen Spector
Xiaobing Shi
Tatiana Kutateladze

Résumé

The inhibitor of apoptosis protein BIRC2 regulates fundamental cell death and survival signaling pathways. Here we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2BIR2 and BIRC2BIR3, to the histone H3 tail and report the structure of the BIRC2BIR3–H3 complex. RNA-seq analysis reveals that the genes involved in interferon and defense response signaling and cell-cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell-cycle progression. We describe the structural mechanism for targeting of BIRC2BIR3 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in human immunodeficiency virus type 1-infected human CD4+ T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.
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Dates et versions

hal-04193895 , version 1 (01-09-2023)

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Adam Tencer, Yucong Yu, Sebastien Causse, Grant Campbell, Brianna Klein, et al.. Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2. Nature Structural and Molecular Biology, 2023, ⟨10.1038/s41594-023-01044-1⟩. ⟨hal-04193895⟩
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