DNA-binding regulates site-specific ubiquitination of IRF-1

Vivien Landré, Emmanuelle Pion, Vikram Narayan, Dimitris P Xirodimas, Kathryn L Ball

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    14 Citations (Scopus)

    Abstract

    Understanding the determinants for site-specific ubiquitination by E3 ligase components of the ubiquitin machinery is proving to be a challenge. In the present study we investigate the role of an E3 ligase docking site (Mf2 domain) in an intrinsically disordered domain of IRF-1 [IFN (interferon) regulatory factor-1], a short-lived IFN?-regulated transcription factor, in ubiquitination of the protein. Ubiquitin modification of full-length IRF-1 by E3 ligases such as CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and MDM2 (murine double minute 2), which dock to the Mf2 domain, was specific for lysine residues found predominantly in loop structures that extend from the DNA-binding domain, whereas no modification was detected in the more conformationally flexible C-terminal half of the protein. The E3 docking site was not available when IRF-1 was in its DNA-bound conformation and cognate DNA-binding sequences strongly suppressed ubiquitination, highlighting a strict relationship between ligase binding and site-specific modification at residues in the DNA-binding domain. Hyperubiquitination of a non-DNA-binding mutant supports a mechanism where an active DNA-bound pool of IRF-1 is protected from polyubiquitination and degradation.
    Original languageEnglish
    Pages (from-to)707-717
    Number of pages11
    JournalBiochemical Journal
    Volume449
    Issue number3
    DOIs
    Publication statusPublished - 1 Feb 2013

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  • Cite this

    Landré, V., Pion, E., Narayan, V., Xirodimas, D. P., & Ball, K. L. (2013). DNA-binding regulates site-specific ubiquitination of IRF-1. Biochemical Journal, 449(3), 707-717. https://doi.org/10.1042/BJ20121076