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ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development

Nature volume 457, pages 906909 (12 February 2009) | Download Citation

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  • A Corrigendum to this article was published on 26 March 2009

Abstract

Proteins that directly regulate tumour necrosis factor receptor (TNFR) signalling have critical roles in regulating cellular activation and survival. ABIN-1 (A20 binding and inhibitor of NF-κB) is a novel protein that is thought to inhibit NF-κB signalling1,2. Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anaemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to tumour necrosis factor (TNF)-induced programmed cell death, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD (Fas-associated death domain-containing protein) in TNF-induced signalling complexes, preventing caspase 8 cleavage and programmed cell death. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1’s anti-apoptotic activity. These studies provide insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.

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Acknowledgements

This work was supported by the NIH (A.M.), UCSF Liver Center Pathology and Flow Cytometry Facilities, UCSF Transgenic and Targeted Mutagenesis Core Facility, a fellowship from the Crohn’s and Colitis Foundation of America (S.O.), a pre-doctoral NSF fellowship (J.A.C.) and the Rainin Foundation.

Author Contributions S.O. and E.E.T. contributed equally to this work. S.O. and J.A.C. performed the cell signalling experiments. J.A.C., E.E.T. and S.O. analysed Tnip1-/- embryos. S.O. performed DISC analyses. E.E.T. performed the ubiquitin binding experiments. E.E.T. and S.C. designed and generated the ABIN-1 gene targeting construct. B.A.M. generated Tnip1-/- ES cells and mice with assistance from S.C. R.A. genotyped and maintained Tnip1-/- mice and performed timed matings. J.B., N.S., B.L. and T.W. performed mutagenesis and generated expression constructs. B.Y. analysed histological and immunohistochemical studies of Tnip1-/- embryos. A.M. and B.A.M. supervised the overall project, and wrote and edited the manuscript.

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Author notes

    • Shigeru Oshima
    •  & Emre E. Turer

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, University of California at San Francisco, 513 Parnassus Avenue, S-1057, San Francisco, California 94143-0451, USA

    • Shigeru Oshima
    • , Emre E. Turer
    • , Joseph A. Callahan
    • , Sophia Chai
    • , Rommel Advincula
    • , Julio Barrera
    • , Nataliya Shifrin
    • , Bettina Lee
    • , Benjamin Yen
    • , Tammy Woo
    • , Barbara A. Malynn
    •  & Averil Ma

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Corresponding author

Correspondence to Averil Ma.

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https://doi.org/10.1038/nature07575

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