Adenovirus E4orf6 assembles with Cullin5-ElonginB-ElonginC E3 ubiquitin ligase through an HIV/SIV Vif-like BC-box to regulate p53.
The adenovirus protein E4orf6 targets p53 for polyubiquitination and proteasomal degradation and is known to form a complex with the Cul5-ElonginB-ElonginC E3 ubiquitin ligase. However, whether Cul5 is directly responsible for the E4orf6-mediated degradation of p53 remains unclear. By using a dominant-negative mutant of Cul5 and silencing Cul5 expression through RNA interference, we have now demonstrated that E4orf6-mediated p53 degradation requires Cul5. Furthermore, we have identified a lentiviral Vif-like BC-box motif in E4orf6 that is highly conserved among adenoviruses from multiple species. More importantly, we have shown that this Vif-like BC-box is essential for the recruitment of Cul5-ElonginB-ElonginC E3 ubiquitin ligase by E4orf6 and is also required for E4orf6-mediated p53 degradation. E4orf6 selectively recruited Cul5 despite the lack of either a Cul5-box, which is used by cellular substrate receptors to recruit Cul5, or a newly identified HCCH zinc-binding motif, which is used by primate lentiviral Vif to recruit Cul5. Therefore, adenovirus E4orf6 molecules represent a novel family of viral BC-box proteins the cellular ancestor of which is as yet unknown.
Luo
Kun
K
Department of Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA.
Ehrlich
Elana
E
Xiao
Zuoxiang
Z
Zhang
Wenyan
W
Ketner
Gary
G
Yu
Xiao-Fang
XF
D017504:Adenovirus E4 Proteins / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D000075065:Elongin; D016346:Gene Products, vif; D006678:HIV; D006801:Humans; D015302:Simian Immunodeficiency Virus; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism / Q000502:physiology; D054320:vif Gene Products, Human Immunodeficiency Virus
D017504:Adenovirus E4 Proteins; C496871:CUL5 protein, human; D044842:Cullin Proteins; D000075065:Elongin; D016346:Gene Products, vif; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases