PROJECT 4 - Vif (PETERLIN AND GROSS. PROJECT LEADERS)The viral infectivity factor Vif is an essential accessory protein of primate lentiviruses, HIV-1, HIV-2,and SIV. Without Vif, these viruses do not replicate in non-permissive cells or in the host. Vif inactivatesthe cellular cytidine deaminases ASF and A3G, which are members of the APOBEC3 (apolipoprotein BmRNA-editing enzyme catalytic-polypeptides 3) family. In the absence of Vif, these APOBEC3 proteinsare incorporated into new viral particles where they deaminate cytidines in the minus-strand cDNA duringreverse transcription. These DNA lesions result in viral DNA degradation or introduction of deleteriousmutations. In addition, the APOBEC3 proteins can inhibit viral replication in the absence of their enzymaticactivity, possibly by altering the reverse transcription process itself. Thus, APOBEC proteins protect cellsagainst HIV, and Vif has evolved to provide an essential viral counter defense.A key role for Vif is to promote ubiquitination and subsequent destruction of A3G and ASF by theproteosome. Vif recruits A3G and ASF to a cellular ubiquitin protein ligase that includes Cullin-5, Ring-box2, and Elongins B and C (EloBC). Even modest inhibition of Vif function, either by interfering with bindingto A3G and/or ASF or by blocking recruitment of the EloBC/Cul5/Rbx2 E3 ligase, might significantly reduceHIV-1 loads in vivo. Therefore, a major objective of this project is to determine the architecture of theVif/EloBC/Cul5/Rbx2 complex and subcomplexes with A3G.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM082250-01
Application #
7480047
Study Section
Special Emphasis Panel (ZRG1-AARR-A (40))
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2007-09-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$421,694
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Faust, Tyler B; Li, Yang; Bacon, Curtis W et al. (2018) The HIV-1 Tat protein recruits a ubiquitin ligase to reorganize the 7SK snRNP for transcriptional activation. Elife 7:
Eckhardt, Manon; Zhang, Wei; Gross, Andrew M et al. (2018) Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network. Cancer Discov 8:1474-1489
Masand, Ruchi; Paulo, Esther; Wu, Dongmei et al. (2018) Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits. Cell Metab 27:616-629.e4
Binning, Jennifer M; Smith, Amber M; Hultquist, Judd F et al. (2018) Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors. PLoS Pathog 14:e1006830
Morris, Kyle L; Buffalo, Cosmo Z; Stürzel, Christina M et al. (2018) HIV-1 Nefs Are Cargo-Sensitive AP-1 Trimerization Switches in Tetherin Downregulation. Cell 174:659-671.e14
Chen, Si-Han; Jang, Gwendolyn M; Hüttenhain, Ruth et al. (2018) CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. EMBO J 37:
Leoz, Marie; Kukanja, Petra; Luo, Zeping et al. (2018) HEXIM1-Tat chimera inhibits HIV-1 replication. PLoS Pathog 14:e1007402
Cheng, Yifan (2018) Single-particle cryo-EM-How did it get here and where will it go. Science 361:876-880
Roth, Theodore L; Puig-Saus, Cristina; Yu, Ruby et al. (2018) Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559:405-409
Ferdin, Jana; Gori?ar, Katja; Dolžan, Vita et al. (2018) Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA. PLoS One 13:e0191613

Showing the most recent 10 out of 199 publications