title: Murine double minute 2 as a modulator of retroviral restrictions mediated by TRIM5alpha.
abstract: In human cells, endogenous TRIM5alpha strongly inhibits N-tropic strains of murine leukemia virus (N-MLV) but does not target the closely related B-MLV. We have used a shRNA-based loss-of-function screen to isolate factors other than TRIM5alpha involved in the restriction of N-MLV. In one of the isolated clones, the shRNA expressed was found to target the murine double minute-2 mRNA. Knocking down MDM2 increased N-MLV and EIAV infection of human cells by 2- to 5-fold while having little effect on B-MLV. Similarly, knocking down MDM2 in African green monkey cells diminished the restriction of both N-MLV and HIV-1. Dual knockdown experiments showed that MDM2 was involved in the restriction mediated by TRIM5alpha. Moreover, MDM2 knockdown decreased the sensitivity of N-MLV infection to treatment with MG132 and As(2)O(3), two known TRIM5alpha pharmacological inhibitors. Altogether, our data suggest that MDM2 is a general but nonessential modulator of TRIM5alpha-mediated antiretroviral functions.
authors.affiliation: Laboratory of retrovirology, University of Québec, Trois-Rivières, Quebec, Canada. marine.malbec@pasteur.fr
authors.forename: Marine
authors.initials: M
authors.lastname: Malbec
authors.forename: Quang Toan
authors.initials: QT
authors.lastname: Pham
authors.forename: Mélodie B
authors.initials: MB
authors.lastname: Plourde
authors.forename: Alexandra
authors.initials: A
authors.lastname: Létourneau-Hogan
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Nepveu-Traversy
authors.forename: Lionel
authors.initials: L
authors.lastname: Berthoux
mesh_terms: D000818:Animals; D000090103:Antiviral Restriction Factors; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D004860:Infectious Anemia Virus, Equine / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D010087:Oxides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D000090103:Antiviral Restriction Factors; D001152:Arsenicals; D002352:Carrier Proteins; D007976:Leupeptins; D010087:Oxides; D000070584:Tripartite Motif Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000077237:Arsenic Trioxide