Mcpip1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling And Inflammation

Keywords

Autoimmunity; Fungal immunity; IL-17; Negative regulation; Regnase-1; Signal transduction

Abstract

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.

Publication Date

9-15-2015

Publication Title

Immunity

Volume

43

Issue

3

Number of Pages

475-487

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.immuni.2015.07.021

Socpus ID

84941732348 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84941732348

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