Summary 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). Using two antibodies specific for acetylated tau, we 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 in vivo, likely 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.

The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 Orf9b, an interaction we structurally characterized using cryo-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

After integration in the host cell genome, the HIV‐1 provirus is packaged into chromatin. A specific chromatin disruption occurs in the HIV‐1 promoter during transcriptional activation in response to TNF‐alpha, suggesting that chromatin plays a repressive role in HIV‐1 transcription and that chromatin modification(s) might result in transcriptional activation. We have treated several cell lines latently infected with HIV‐1 with two new specific inhibitors of histone deacetylase, trapoxin (TPX) and trichostatin A (TSA), to cause a global hyperacetylation of cellular histones. Treatment with both drugs results in the transcriptional activation of the HIV‐1 promoter and in a marked increase in virus production. Dose‐response curves and kinetic analysis show a close correlation between the level of histone acetylation and HIV‐1 gene expression. In contrast, both TPX and TSA have little or no effect on HIV‐1 promoter activity following transient transfection of an HIV‐1 promoter‐reporter plasmid. Activation of HIV‐1 transcription by TSA and TPX treatment occurs in the absence of NF‐kappa B induction. Chromatin analysis of the HIV‐1 genome shows that a single nucleosome (nuc‐1) located at the transcription start and known to be disrupted following TNF‐alpha treatment, is also disrupted following TPX or TSA treatment. This disruption is independent of transcription as it is resistant to alpha‐amanitin. These observations further support the crucial role played by nuc‐1 in the suppression of HIV‐1 transcription during latency and demonstrate that transcriptional activation of HIV‐1 can proceed through a chromatin modification.