The E3 Ligase TRAF6 directs FOXP3 localization and facilitates Treg function through K63‐type ubiquitination

Abstract

For the immune system to function properly, the activation of leukocytes must be tightly regulated. Failures of immune control mechanisms underlie the aberrant targeting of self‐antigens (i.e. autoimmunity) and the collateral damage of healthy tissues during excessive responses to infectious threats or the unnecessary immune mobilization against innocuous commensal microbes. Foxp3‐expressing CD4+ Regulatory T cells (Tregs) are a major cellular force working to prevent these pathologies of immune dysregulation. These cells characteristically exhibit multiple suppressive function that is absolutely required for the maintenance of immune homeostasis. However, these cells can hamper desirable anti‐tumor immune responses in cancer patients. Accordingly, a relative abundance of Tregs in the tumor microenvironment (TME) is a negative prognostic factor in many cancers. Treg‐depleting or antagonizing strategies show promise as potential interventions capable of unleashing anti‐tumor immunity from suppression. The characteristic gene expression and suppressive function of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. While transcriptional regulation of the Foxp3gene has been studied in depth, both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. We have found that in the absence of the E3 ligase TRAF6 Tregs were dysfunctional in vivo. In these studies, mice with Treg‐restricted deletion of TRAF6 were highly resistant to implanted tumors and displayed enhanced anti‐tumor immunity. We further determined that FOXP3 undergoes lysine‐63 linked (K63) ubiquitination at lysine 262, and this posttranslational modification was mediated by TRAF6. When deprived of TRAF6 activity or rendered insensitive to K63 ubiquitination, FOXP3 displayed aberrant, perinuclear accumulation and disrupted regulatory function. Thus, K63 ubiquitination by TRAF6 ensures proper localization of FOXP3 and facilitates the transcription factor's gene‐regulating activity in Tregs. These results implicate TRAF6 as a key, hitherto unappreciated posttranslational facilitator of FOXP3 stabilization and Treg suppressive function that may be targeted by novel tolerance‐breaking immunotherapies to improve anti‐tumor immunity and combat disease progression in cancer patients.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.