Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered in 1963 as a unique modification of histones, acetylation marks are now found on thousands of nonhistone proteins located in virtually every cellular compartment. Here we summarize key findings in the field of protein acetylation over the past 20 years with a focus on recent discoveries in nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these findings have elevated protein acetylation as a major post-translational modification, underscoring its physiological relevance in gene regulation, cell signaling, metabolism, and disease.

SUMMARY A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat as well as via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of, CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.

SUMMARY BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells and was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BAF, a SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromo- and ET domains and was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using ChIP-seq combined with ATAC-seq data, we found that the latent HIV-1 promoter phenotypically resembles endogenous LTR sequences, pointing to a select role of BRD4S:BRG1 complexes in genomic silencing of invasive retroelements.