mTOR has emerged as an important regulator of T helper cell differentiation. Here we demonstrate that TH1 and TH17 differentiation is selectively regulated by Rheb-dependent mTOR complex 1 (mTORC1) signaling. Rheb-deficient T cells fail to generate TH1 and TH17 responses in vitro and in vivo and cannot induce classical experimental autoimmune encephalomyelitis (EAE). However, they retain their ability to become TH2 cells. Alternatively, when mTORC2 signaling is deleted in T cells, they fail to generate TH2 cells in vitro and in vivo but preserve their ability to become TH1 and TH17 cells. Our data provide mechanisms by which the two distinct signaling pathways downstream of mTOR differentially regulate helper cell fate. These findings define a novel paradigm linking T cell differentiation with selective metabolic signaling pathways.

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.

Summary The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. While p300 inhibitors have been reported, a potent, selective, and readily available active-site directed small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone-containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anti-cancer target.