The Ubiquitin Ligase Stub1 Negatively Modulates Regulatory T Cell Suppressive Activity by Promoting Degradation of the Transcription Factor Foxp3

Abstract

SUMMARY Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharide lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo, and conferred a T helper 1 (Th1) cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection and cancer.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…5d). Ubiquitylation of FOXP3, RORγt and T-bet controls transcription factor stability, and dysregulation of the ubiquitylating or de-ubiquitylating enzymes can induce phenotypic plasticity in these cells [183][184][185] . Blocking the activity of sirtuin 1 preserves FOXP3 acetylation, enhancing FOXP3 stability and T Reg cell function 186,187 , whereas inhibition of sirtuin 1 increases RORγt acety lation in T H 17 cells, which impedes RORγt activity 188 , thus creating another therapeutically exploitable dichotomy between inflammatory and regulatory cells.…”

FOXP3+ regulatory T cells and their functional regulation

“…30 On the molecular level, we have identified how the stress-activated Stub1-Hsp70 complex plays a critical role in the degradation of FOXP3 and promotion of Treg cell conversion into Th1-like cells. 31 All these observations indicate that FOXP3 1 Treg cells may be unstable and can convert into Thlike Treg cells in response to certain immunological environments.…”

“…74 Subsequently, FOXP3 was also found to undergo ubiquitination and the that ubiquitination would lead to its degradation. 31,55 Since both ubiquitination and acetylation are restricted to lysine residues, acetylation may compete with poly-ubiquitination to stabilize FOXP3. 57 Two acetyltransferases, Tip60 and p300, have been reported as enzymes that are responsible for FOXP3 acetylation.…”

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

“…The key reason is that inflammatory cytokines, such as IL-6, TNF-a and IL-1, may decrease Foxp3 expression and subsequently reduce the functional activity of nTreg cells. 22,23,[32][33][34][35][36] THE STABILITY OF TREG CELL SUBSETS Recent studies demonstrated that nTreg cells from both mouse and human are instable and dysfunctional under inflammatory conditions. 7,32,34,35,37,38 These cells not only lose their suppressive ability after encountering inflammatory environments, but they can convert into pathogenic cells that may actually accelerate the inflammatory process.…”