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

Research output: Contribution to journalArticle

15 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
DOIs
Publication statusPublished - Nov 5 2013

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Cullin Proteins
Proteolysis
Ligases
Hypoxia-Inducible Factor 1
Von Hippel-Lindau Tumor Suppressor Protein
SUMO-1 Protein
Proteins
Cytokines
Viral Proteins
Proteasome Endopeptidase Complex
Ubiquitin
elongin
Protein Domains
Enzymes

Keywords

  • Hypoxia
  • Oncoviral proteins
  • Ubiquitylation

ASJC Scopus subject areas

  • General

Cite this

BC-box protein domain-related mechanism for VHL protein degradation. / Pozzebon, Maria Elena; Varadaraj, Archana; Mattoscio, Domenico; Jaffray, Ellis G.; Miccolo, Claudia; Galimberti, Viviana; Tommasino, Massimo; Hay, Ronald T.; Chiocca, Susanna.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 45, 05.11.2013, p. 18168-18173.

Research output: Contribution to journalArticle

Pozzebon, Maria Elena ; Varadaraj, Archana ; Mattoscio, Domenico ; Jaffray, Ellis G. ; Miccolo, Claudia ; Galimberti, Viviana ; Tommasino, Massimo ; Hay, Ronald T. ; Chiocca, Susanna. / BC-box protein domain-related mechanism for VHL protein degradation. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 45. pp. 18168-18173.
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