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

Nature Structural & Molecular Biology volume 30, pages 1265–1274 (2023)Cite this article

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Abstract

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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Fig. 1: BIRC2 recognizes histone tails.
Fig. 2: BIRs mediate histone and DNA binding functions of BIRC2.
Fig. 3: BIRC2 mediates cell defense and cell-cycle signaling.
Fig. 4: LCL161 binds to BIRC2BIR2 and BIRC2BIR3.
Fig. 5: LCL161 disrupts binding of BIRC2 to H3 and induces cell death.
Fig. 6: LCL161 mediates BIRCs degradation in HIV-1-infected CD4+ T cells.

Data availability

Coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 7TRL and 7TRM. RNA-seq data are deposited in the NCBI Gene Expression Omnibus (GEO) database with the accession number GSE23028. Source data and Supplementary Data files are provided with this paper. All other relevant data supporting the key findings of this study are available within the article, its Supplementary Information or from the corresponding authors upon reasonable request.

Code availability

This paper does not report original code.

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Acknowledgements

This work was supported in part by grants from the NIH nos. GM125195, GM135671, HL151334, CA252707 and AG067664 to T.G.K., nos. CA204020 and CA268440 to X.S., nos. MH128021 to G.R.C., nos. NS104015 to S.A.S. and no. CA255506 to H.W., by the Ligue Contre le Cancer to L.D., the European Union and the ‘Conseil Régional de Bourgogne,’ a French Government grant managed by the French National Research Agency under the program ‘Investissements d’Avenir’ (ANR-11-LABX-0021) to L.D. and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (impaactnetwork.org) to S.A.S. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network is provided by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. These authors contributed equally: Adam H. Tencer, Yucong Yu, Sebastien Z. Causse, Grant R. Campbell.

Authors and Affiliations

  1. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

    Adam H. Tencer, Brianna J. Klein, Nitika Gaurav, Tina A. Holt & Tatiana G. Kutateladze

  2. Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA

    Yucong Yu, Hongwen Xuan, Hong Wen & Xiaobing Shi

  3. Institut National de la Santé et de la Recherche Médicale (Inserm), LNC UMR1231, Dijon, France and Université de Bourgogne Franche-Comté, Dijon, France

    Sebastien Z. Causse, Jessy Cartier, Aymeric Zadoroznyj & Laurence Dubrez

  4. Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

    Grant R. Campbell & Stephen A. Spector

  5. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA

    Grant R. Campbell

  6. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia

    Mark A. Miles & Christine J. Hawkins

  7. Rady Children’s Hospital, San Diego, CA, USA

    Stephen A. Spector

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Contributions

A.H.T., Y.Y., S.Z.C., G.R.C., B.J.K., H.X., J.C., M.A.M., N.G., A.Z. and T.A.H. performed experiments and, together with H.W., C.J.H., S.A.S., L.D., X.S. and T.G.K., analyzed the data. T.G.K. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Stephen A. Spector, Laurence Dubrez, Xiaobing Shi or Tatiana G. Kutateladze.

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Nature Structural & Molecular Biology thanks Francisco Blanco, Ji-Joon Song and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Carolina Perdigoto, in collaboration with the Nature Structural & Molecular Biology team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–9.

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Supplementary Data

Source data for supplementary information.

Supplementary Table 1

CPM values for all expressed genes and GO biological process terms of DEGs in BIRC2 KO cells. Adjusted P values for DEGs were calculated by two-sided Exact test model.

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Source Data Figs. 1 and 3–6

Fluorescence, G2/M, RT–qPCR, MTT, LDH and ELISA data.

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Tencer, A.H., Yu, Y., Causse, S.Z. et al. Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2. Nat Struct Mol Biol 30, 1265–1274 (2023). https://doi.org/10.1038/s41594-023-01044-1

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