The lysine methyltransferase SMYD5 amplifies HIV-1 transcription and is post-transcriptionally upregulated by Tat and USP11

Abstract

A successful HIV-1 cure strategy may require enhancing HIV-1 latency to silence HIV-1 transcription. Modulators of gene expression show promise as latency-promoting agents invitro and invivo. Here, we identify Su(var)3-9, enhancer-of-zeste, and trithorax (SET) and myeloid, Nervy, and DEAF-1 (MYND) domain-containing protein 5 (SMYD5) as a host factor required for HIV-1 transcription. SMYD5 is expressed in CD4+ Tcells and activates the HIV-1 promoter with or without the viral Tat protein, while knockdown of SMYD5 decreases HIV-1 transcription in cell lines and primary Tcells. SMYD5 associates invivo with the HIV-1 promoter and binds the HIV trans-activation response (TAR) element RNA and Tat. Tat is methylated by SMYD5 invitro, and in cells expressing Tat, SMYD5 protein levels are increased. The latter requires expression of the Tat cofactor and ubiquitin-specific peptidase 11 (USP11). We propose that SMYD5 is a host activator of HIV-1 transcription stabilized by Tat and USP11 and, together with USP11, a possible target for latency-promoting therapy.