FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-γ/TNF-α-mediated cytotoxicity

Qishen Pang, Winifred Keeble, Tracy A. Christianson, Gregory R. Faulkner, Grover C. Bagby

    Research output: Contribution to journalArticle

    110 Scopus citations

    Abstract

    The Fanconi anemia (FA) complementation group C gene product (FANCC) functions to protect hematopoietic cells from cytotoxicity induced by interferon-α (IFN-γ), tumor necrosis factor-α (TNF-α) and doublestranded RNA (dsRNA). Because apoptotic responses of mutant FA-C cells involve activation of interferoninducible, dsRNA-dependent protein kinase PKR, we sought to identify FANCC-binding cofactors that may modulate PKR activation. We identified the molecular chaperone Hsp70 as an interacting partner of FANCC in lymphoblasts and HeLa cells using 'pull-down' and co-immunoprecipitation experiments. In vitro binding assays showed that the association of FANCC and Hsp70 involves the ATPase domain of Hsp70 and the central 320 residues of FANCC, and that both Hsp40 and ATP/ADP are required. In whole cells, Hsp70-FANCC binding and protection from IFN-γ/TNF-α-induced cytotoxicity were blocked by alanine mutations located in a conserved motif within the Hsp70-interacting domain of FANCC. We therefore conclude that FANCC acts in concert with Hsp70 to prevent apoptosis in hematopoietic cells exposed to IFN-γ and TNF-α.

    Original languageEnglish (US)
    Pages (from-to)4478-4489
    Number of pages12
    JournalEMBO Journal
    Volume20
    Issue number16
    DOIs
    StatePublished - Aug 15 2001

    Keywords

    • FANCC
    • Fanconi anemia
    • Hsp70/IFN-γ and TNFα cytotoxicity
    • Protective function

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Molecular Biology
    • Biochemistry, Genetics and Molecular Biology(all)
    • Immunology and Microbiology(all)

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