Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression

Abstract

The molecular mechanism by which roquin controls the expression of inducible costimulator (ICOS) to prevent autoimmunity remains unsolved. Here we show that in helper T cells, roquin localized to processing (P) bodies and downregulated ICOS expression. The repression was dependent on the RNA helicase Rck, and roquin interacted with Rck and the enhancer of decapping Edc4, which act together in mRNA decapping. Sequences in roquin that confer P-body localization were essential for roquin-mediated ICOS repression. However, this process did not require microRNAs or the RNA-induced silencing complex (RISC). Instead, roquin bound ICOS mRNA directly, showing an intrinsic preference for a previously unrecognized sequence in the 3' untranslated region (3' UTR). Our results support a model in which roquin controls ICOS expression through binding to the 3' UTR of ICOS mRNA and by interacting with proteins that confer post-transcriptional repression.

Roquin binding to target mRNAs involves a winged helix-turn-helix motif

“…As indicated by our analytical ultracentrifugation experiments, monomeric ROQUIN1 predominates at lower protein concentrations, but a concentration-dependent dimerization of Roquin has been reported by Schlundt et al 20 Since Roquin proteins accumulate in P bodies and stress granules 3,21 , it is tempting to speculate that elevated Roquin concentration at these sites might favour the formation of functional dimers.…”

“…1). The expression of ICOS (inducible T-cell costimulator), a gene encoding an essential receptor for follicular T-cells, is also restricted by Roquin, which promotes the degradation of ICOS mRNA, thereby playing an important role in autoimmunity 2,3 .…”

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

“…The alternative splicing of CD45RA to CD45RO is one of the hallmarks of memory T-cell differentiation (28). The stability of ICOS mRNA, which is governed by the RBPs Roquin-1 and -2, restrains the differentiation of follicular helper T cells (29)(30)(31)(32)(33). The RBPs Zfp36l1 and Zfp36l2 suppress Notch1 mRNA stability, regulating normal thymocyte differentiation and preventing malignant transformation (34).…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…However, some studies showed that roquin represses autoimmunity by limiting ICOS mRNA expression through a microRNA-independent posttranslational repression. 33,34 In addition, a recent study showed that the loss of roquin induced early death and immune dysregulation but not autoimmunity in sanroque mice. 35 Therefore, future studies are required to completely elucidate the mechanisms behind pathogenesis of lupus in sanroque mice.…”