Murine double minute 2 as a modulator of retroviral restrictions mediated by TRIM5α

In human cells, endogenous TRIM5 alpha 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 TRIM5a 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 TRIM5a. Moreover, MDM2 knockdown decreased the sensitivity of N-MLV infection to treatment with MG132 and As2O3, two known TRIM5a pharmacological inhibitors. Altogether, our data suggest that MDM2 is a general but nonessential modulator of TRIM5 alpha-mediated antiretroviral functions. (C) 2010 Elsevier Inc. All rights reserved.