An autoimmune
transcriptional circuit drives FOXP3+ regulatory T cell dysfunction Autoimmune diseases are mediated by genetic and
environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) are known
to be dysfunctional in autoimmune diseases and play a central role in
preventing autoimmunity, the molecular mechanism underlying their dysfunction
is unknown. By performing comprehensive transcriptomic and epigenomic profiling
of Tregs in multiple sclerosis (MS), an autoimmune disease of the central nervous system, the
author identified critical transcriptional programs regulating human
autoimmunity. The up-regulation of a primate-specific short isoform of PR
domain zinc finger protein 1 (PRDM1-S) was independent from the evolutionarily
conserved long PRDM1, and induced expression of serum and
glucocorticoid-regulated kinase 1 (SGK1), which led to destabilization of FOXP3
and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis also existed among other
autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs revealed
enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF)
transcription factor binding as candidate upstream regulators in this circuit. The
evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key
drivers of dysfunctional Tregs in autoimmune diseases.DOI: 10.1126/scitranslmed.adp1720
N-acetyltransferase 10 is
implicated in the pathogenesis of cycling T cell-mediated autoimmune and
inflammatory disorders in mice![]()
Li W. et al.
T cell expansion has a crucial function in both
autoimmune and chronic inflammatory diseases, with cycling T cells contributing
to the pathogenesis of autoimmune diseases by causing uncontrolled immune
responses and tissue damage. Yet the regulatory mechanisms governing T cell
expansion remain incompletely understood. Here the authors show that the enzyme
N-acetyltransferase 10 (NAT10) regulates T cell activation and proliferation
upon antigen stimulation. T cell-specific NAT10 deficiency in mice reduces the
number of mature T cells in peripheral lymphoid organs. Mechanistically, NAT10
acetylates RACK1 at K185, preventing subsequent RACK1 K48-linked ubiquitination
and degradation. The increased RACK1 stability alters ribosome formation and
cellular metabolism, leading to enhanced supply of energy and biosynthetic
precursors and, eventually, T cell proliferation. These findings highlight the
essential function of NAT10 in T cell self-renewal and metabolism and elucidate
NAT10 mode of action for the potential development of novel therapies for
immune-related disorders.
DOI: 10.1038/s41467-024-53350-x
Editor & Reviewer: Shiyang Song
