title: Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G.
abstract: Cellular restriction factors help to defend humans against human immunodeficiency virus (HIV). HIV accessory proteins hijack at least three different Cullin-RING ubiquitin ligases, which must be activated by the small ubiquitin-like protein NEDD8, in order to counteract host cellular restriction factors. We found that conjugation of NEDD8 to Cullin-5 by the NEDD8-conjugating enzyme UBE2F is required for HIV Vif-mediated degradation of the host restriction factor APOBEC3G (A3G). Pharmacological inhibition of the NEDD8 E1 by MLN4924 or knockdown of either UBE2F or its RING-protein binding partner RBX2 bypasses the effect of Vif, restoring the restriction of HIV by A3G. NMR mapping and mutational analyses define specificity determinants of the UBE2F NEDD8 cascade. These studies demonstrate that disrupting host NEDD8 cascades presents a novel antiretroviral therapeutic approach enhancing the ability of the immune system to combat HIV.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stanley
authors.forename: Koen
authors.initials: K
authors.lastname: Bartholomeeusen
authors.forename: David C
authors.initials: DC
authors.lastname: Crosby
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Eunju
authors.initials: E
authors.lastname: Kwon
authors.forename: Linda
authors.initials: L
authors.lastname: Yen
authors.forename: Nathalie Caretta
authors.initials: NC
authors.lastname: Cartozo
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jäger
authors.forename: Jeremy
authors.initials: J
authors.lastname: Mason-Herr
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Hayashi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: Boris Matija
authors.initials: BM
authors.lastname: Peterlin
authors.forename: John D
authors.initials: JD
authors.lastname: Gross
mesh_terms: D000071480:APOBEC-3G Deaminase; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism*; D003517:Cyclopentanes / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism*; D057809:HEK293 Cells; D006678:HIV / Q000254:growth & development / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D008279:Magnetic Resonance Imaging; D000075687:NEDD8 Protein; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: C496871:CUL5 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; C479529:RBX1 protein, human; D034741:RNA, Small Interfering; D014452:Ubiquitins; D054320:vif Gene Products, Human Immunodeficiency Virus; C118307:RNF7 protein, human; D044767:Ubiquitin-Protein Ligases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; C539933:pevonedistat