title: BC-box protein domain-related mechanism for VHL protein degradation.
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 proteasome-dependent 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Pozzebon
authors.forename: Archana
authors.initials: A
authors.lastname: Varadaraj
authors.forename: Domenico
authors.initials: D
authors.lastname: Mattoscio
authors.forename: Ellis G
authors.initials: EG
authors.lastname: Jaffray
authors.forename: Claudia
authors.initials: C
authors.lastname: Miccolo
authors.forename: Viviana
authors.initials: V
authors.lastname: Galimberti
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Hay
authors.forename: Susanna
authors.initials: S
authors.lastname: Chiocca
mesh_terms: D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000075065:Elongin; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism* / Q000502:physiology
chemical_list: C105052:CELO protein, adenovirus; D044842:Cullin Proteins; D017931:DNA Primers; C000616396:ELOB protein, human; D000075065:Elongin; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D008156:Luciferases; D043743:Ubiquitin-Protein Ligase Complexes; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: hypoxia; oncoviral proteins; ubiquitylation