The E3 ligase Hrd1 is crucial in maintaining Treg cells

T regulatory (Treg) cells play an essential role in maintaining peripheral tolerance and preventing autoimmune diseases. However, the exact molecular mechanisms underlying Treg cell regulation remain unclear. Here, we show that the E3 ubiquitin ligase Hrd1 is essential for Treg cell homeostasis and function. Mice with Treg cell-specific ablation of Hrd1 displayed massive multi-organ lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. Consistent with uncontrolled inflammatory responses in Hrd1-/- mice, the expression of anti-inflammatory IL10 cytokines by Hrd1-/- Treg cells was dramatically reduced under both steady-state and inflammatory conditions. In addition, TGFβ treatment of Hrd1-/- T cells induced less FoxP3 expression and functionally, these TGFβ converted Hrd1-/- Treg cells were unable to suppress colitis in vivo, implying that Hrd1 was essential for TGFβ induced Treg differentiation and suppressive functions. At the molecular level, Hrd1 associated with and promoted conjugation of ubiquitin to the Smad7 protein, a TGFβ induced molecule that antagonizes TGFβ signaling pathway. As a consequence, TGFβR1 was downregulated by Hrd1-deficency and subsequently impaired Smad2/Smad3 mediated TGFβ signal transduction. These findings indicate that regulation of TGFβ signaling pathway by Hrd1 is crucial to maintain the generation and suppressive function of FoxP3+ Treg cells.