In 1964, Vincent Allfrey and colleagues reported the identification of histone acetylation and with deep insight proposed a regulatory role for this protein modification in transcription regulation. ...Subsequently, histone acetyltransferases (HATs), histone deacetylases (HDACs) and acetyl-Lys-binding proteins were identified as transcription regulators, thereby providing compelling evidence for his daring hypothesis. During the past 15 years, reversible protein acetylation and its modifying enzymes have been implicated in many cellular functions beyond transcription regulation. Here, we review the progress accomplished during the past 50 years and discuss the future of protein acetylation.
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.
Thirteen years ago, human cyclin T1 was identified as part of the positive transcription elongation factor b (P-TEFb) and the long-sought host cofactor for the HIV-1 transactivator Tat. Recent years ...have brought new insights into the intricate regulation of P-TEFb function and its relationship with Tat, revealing novel mechanisms for controlling HIV transcription and fueling new efforts to overcome the barrier of transcriptional latency in eradicating HIV. Moreover, the improved understanding of HIV and Tat forms a basis for studying transcription elongation control in general. Here, we review advances in HIV transcription research with a focus on the growing family of cellular P-TEFb complexes, structural insights into the interactions between Tat, P-TEFb, and TAR RNA, and the multifaceted regulation of these interactions by posttranscriptional modifications of Tat.
SARS-CoV-2, the virus causing the current COVID-19 pandemic, primarily targets the airway epithelium and in lungs can lead to acute respiratory distress syndrome. Clinical studies in recent months ...have revealed that COVID-19 is a multi-organ disease causing characteristic complications. Stem cell models of various organ systems—most prominently, lung, gut, heart, and brain—are at the forefront of studies aimed at understanding the role of direct infection in COVID-19 multi-organ dysfunction.
Simoneau and Ott discuss various stem-cell-derived models used to elucidate susceptibility of different organ systems to SARS-CoV-2, exploring their permissiveness to viral infection, consequent innate immune responses, and the disruption of essential cellular functions.
Efforts to determine why new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants demonstrate improved fitness have been limited to analyzing mutations in the spike (S) protein with ...the use of S-pseudotyped particles. In this study, we show that SARS-CoV-2 virus-like particles (SC2-VLPs) can package and deliver exogenous transcripts, enabling analysis of mutations within all structural proteins and at multiple steps in the viral life cycle. In SC2-VLPs, four nucleocapsid (N) mutations found universally in more-transmissible variants independently increased messenger RNA delivery and expression ~10-fold, and in a reverse genetics model, the serine-202→arginine (S202R) and arginine-203→methionine (R203M) mutations each produced >50 times as much virus. SC2-VLPs provide a platform for rapid testing of viral variants outside of a biosafety level 3 setting and demonstrate N mutations and particle assembly to be mechanisms that could explain the increased spread of variants, including B.1.617.2 (Delta, which contains the R203M mutation).
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 it 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 BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and this isoform was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using chromatin immunoprecipitation sequencing (ChIP-seq) combined with assay for transposase-accessible chromatin coupled to high-throughput sequencing (ATAC-seq) data, we found that the latent HIV-1 promoter phenotypically resembles endogenous long terminal repeat (LTR) sequences, pointing to a select role of BRD4S-BRG1 complexes in genomic silencing of invasive retroelements.
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•The short isoform of BRD4 is a corepressor of HIV transcription during latency•BET inhibition disrupts SWI/SNF nucleosome remodelers at the latent HIV promoter•Short BRD4 directly binds the BRG1 ATPase to tether SWI/SNF to latent HIV chromatin•Endogenous LTR-containing retroelements are co-occupied by BRD4 and BRG1
BET protein inhibition can reverse HIV latency, yet the long isoform of BRD4 is a well-characterized transcriptional co-activator. Conrad et al. find that the short isoform of BRD4 cooperates with SWI/SNF nucleosome remodelers to repress HIV transcription during latency, a phenotype reversed by BET inhibitor treatment.
Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following ...Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.
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•In breakthrough infections, variant-specific cross-neutralizing immunity is limited•Higher antibody titers are observed in severe versus mild breakthrough infections•Delta breakthroughs exhibited 10.8× higher antibody titers compared with Omicron•The rise in antibody titers from Omicron breakthroughs was 1/3 of that from boosting
In comparing breakthrough infections from the SARS-CoV-2 Delta and Omicron variants, the latter, though milder than Delta infections, were associated with lower antibody titers and limited cross-neutralizing immunity, suggesting reduced protection against reinfection or infection from a future variant.
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 in vitro and in vivo. 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+ T cells 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 T cells. SMYD5 associates in vivo with the HIV-1 promoter and binds the HIV trans-activation response (TAR) element RNA and Tat. Tat is methylated by SMYD5 in vitro, 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.
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•Lysine methyltransferase SMYD5 knockdown inhibits HIV-1 reactivation from latency•SMYD5 associates with the HIV-1 LTR and activates transcription•RNA Pol II and CDK9 associate in a SMYD5-dependent manner with the HIV-1 LTR•SMYD5 methylates Tat and is stabilized by Tat through USP11
The data presented here connect the lysine methyltransferase SMYD5 with HIV-1 transcription. Boehm et al. propose that SMYD5 is a host coactivator of HIV-1 transcription by itself but is also stabilized by the viral Tat protein and the ubiquitin-specific peptidase 11 (USP11) and a possible target for latency-promoting therapy.
Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau ...levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). We generated two antibodies specific for acetylated tau and showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau, probably by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.
► Tau is acetylated and tau acetylation is elevated at early stage of tauopathy ► SIRT1 deacetylates tau, whereas p300 mediates tau acetylation ► Tau acetylation slows down its degradation ► Enhancing tau deacetylation abolishes pathogenic forms of phosphorylated tau
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