BC-box protein domain-related mechanism for VHL protein degradation

Maria Elena Pozzebon, Archana Varadaraj, Domenico Mattoscio, Ellis G. Jaffray, Claudia Miccolo, Viviana Galimberti, Massimo Tommasino, Ronald T. Hay, Susanna Chiocca (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)

    Abstract

    The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasomedependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.

    Original languageEnglish
    Pages (from-to)18168-18173
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number45
    Early online date21 Oct 2013
    DOIs
    Publication statusPublished - 5 Nov 2013

    Keywords

    • Hypoxia
    • Oncoviral proteins
    • Ubiquitylation

    ASJC Scopus subject areas

    • General

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