Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G

Title
Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G
Author(s)
David J. Stanley[David J. Stanley]Koen Bartholomeeusen[Koen Bartholomeeusen]David C. Crosby[David C. Crosby]김동영권은주[권은주]Linda Yen[Linda Yen]Nathalie Caretta Cartozo[Nathalie Caretta Cartozo]Ming Li[Ming Li]Stefanie Jaeger[Stefanie Jaeger]Jeremy Mason-Herr[Jeremy Mason-Herr]Fumiaki Hayashi[Fumiaki Hayashi]Shigeyuki Yokoyama[Shigeyuki Yokoyama]Nevan J. Krogan[Nevan J. Krogan]Reuben S. Harris[Reuben S. Harris]Boris Matija Peterlin[Boris Matija Peterlin]John D. Gross[John D. Gross]
Keywords
UBIQUITIN-CONJUGATING ENZYME; T-CELL DIFFERENTIATION; CULLIN-RING LIGASES; VIRUS TYPE-1 VIF; CBF-BETA; STRUCTURAL INSIGHTS; PROTEIN; COMPLEX; INFECTION; RNA
Issue Date
201212
Publisher
PUBLIC LIBRARY SCIENCE
Citation
PLOS PATHOGENS, v.8, no.12
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.
URI
http://hdl.handle.net/YU.REPOSITORY/26748http://dx.doi.org/10.1371/journal.ppat.1003085
ISSN
1553-7374
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약학대학 > 약학부 > Articles
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