Roquin--a multifunctional regulator of immune homeostasis

Abstract

Roquin-1 (Rc3h1) is an E3 ubiquitin ligase originally discovered in a mutational screen for genetic factors contributory to systemic lupus erythematosus-like symptoms in mice. A single base-pair mutation in the Rc3h1 gene resulted in the manifestation of autoantibody production and sustained immunological inflammation characterized by excessive T follicular helper cell activation and formation of germinal centers. Subsequent studies have uncovered a multifactorial process by which Roquin-1 contributes to the maintenance of immune homeostasis. Through its interactions with partner proteins, Roquin-1 targets mRNAs for decay with inducible costimulator being a primary target. In this review, we discuss newly discovered functions of Roquin-1 in the immune system and inflammation, and in disease manifestation, and discuss avenues of further research. A model is presented for the role of Roquin in health and disease.

Figure 1

(Top panel) Mesenteric lymph node T cells were cultured in the presence of control Ig, anti-CD3 antibody, or a cocktail for stimulation of Th17 cells. T cell stimulation by either pan-T cell activation or Th-17 cell activation resulted in decreased Rc3h1 gene expression, suggesting that during the normal process of T cell immune activation, Rc3h1 expression is suppressed. (Bottom panel) Confirmation that Th17 stimulation specifically induces Th17 gene expression.

Figure 2

A model of a biphasic role for Roquin during the expansion and contraction phases of the immune response. Upon encounter with foreign antigen, Rc3h1 gene expression is suppressed by the IKZF2 (and possibly other) transcription factor, down-regulating Roquin-1 protein expression. Concomitantly, Malt1 blocks Reg1, Roquin-1, and Roquin-2 proteins intracellularly, leading to increased surface expression of ICOS and a robust immune response. Upon removal of immune stimuli, and possibly due to immune-modulating cytokines such as IL-10, the Rc3h1 gene is transcriptionally upregulated by STAT1, STAT3, c-Rel, and GATA2. Malt1 activity also may be suppressed. Rc3h1 gene expression and Roquin-1 block miR146a and suppress surface ICOS expression. Contributing to this process is CTLA4, which competes for binding to the CD28 ligands, CD80 and CD86. Failure to re-activate Rc3h1 gene expression would result in elevated ICOS expression, however, potentially leading to autoimmunity and chronic inflammation.