MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation

Abstract

SUMMARY Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly, but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3’ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…51 More recently, a study showed that another DUB [MCPIP1 (also named Regnase-1)] served as a negative regulator of IL-17 signaling. 53 Unexpectedly, its endoribonuclease but not its deubiquitinase activity was required for the suppression of IL-17 signaling. Mechanically, MCPIP1 inhibits IL-17-mediated signaling and inflammation by degrading the Il6, Nfkbiz, Il17ra and Il17rc mRNAs.…”

“…Mechanically, MCPIP1 inhibits IL-17-mediated signaling and inflammation by degrading the Il6, Nfkbiz, Il17ra and Il17rc mRNAs. 53 IL-17B and IL-17E IL-17RB (also designated IL-17BR or IL-17Rh1) is the receptor for IL-17E. 28 Despite its lower binding affinity compared with IL-17E, IL-17B has also been reported to be a ligand for IL-17RB.…”

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

“…NF-kB regulates the gene promoter activity of ABIN-1, inducing its mRNA as a late expression gene compared with the A20 expression after TNF-a stimulation (13,24). These data thus suggested that ABIN-1 is part of a similar negative feedback loop, analogous to other IL-17 signaling inhibitors such as A20 and MCP1-induced protein 1/Regnase-1 (7,36). Indeed, in HeLa cells NF-kB was found to induce expression of ABIN-1, whereas ABIN-1 in turn repressed NF-kB activity (13).…”

MCPIP mediates preconditioning protection against ischemia

“…In addition to this down regulation of inflammation via the deubiquinase activity of MCPIP, the RNase activity of MCPIP destabilizes and causes degradation of the transcripts of inflammatory cytokines such as IL-1β and IL-6 by binding to the stem loop structure at 3'-UTR of the mRNA 21 . MCPIP can also degrade 3'-UTR-independent degradation of mRNA of the receptors of inflammatory cytokines such as IL-17 22 . Even though RNase activity-dependent degradation of IL-17 receptor transcript was shown to be independent of its UTR, the structural features of the transcript involved in the binding and degradation of IL-17 receptors remain unknown.…”

“…Deubiquiniase activity inhibits NF-κB activation and probably regulates the ubiquitination state of proteins that can determine their subcellular localization, function and fate. The RNase activity destabilizes and enhances degradation of mRNA for inflammatory cytokine and their receptors 21,22 . The anti-Dicer RNase activity inhibits synthesis of microRNAs (miRs) that can influence cellular function in many ways 25 .…”