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

ABSTRACT: The inhibitor of apoptosis protein (IAP) BIRC2 regulates fundamental cell death and survival signaling pathways. Aberrant activity of BIRC2 is associated with immunological diseases, inflammation, and cancer. Unlike other IAPs, BIRC2 can localize to and function in the nucleus through unknown mechanisms. Here, we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2BIR2 and BIRC2BIR3, to histone H3 tail and report the crystal structure of the BIRC2BIR3:H3 complex. RNA-seq analysis of cells in which the BIRC2 gene is knocked out by CRISPR/Cas9 reveals that the genes involved in the interferon and defense response signaling and the cell cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell cycle progression and extends the etoposide-induced G2/M cell cycle arrest. 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 readily stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in HIV-1 infected human CD4+ T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230283 | GEO | 2023/04/21

REPOSITORIES: GEO

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