MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2015-09-15
Date Acceptance
2015-06-16
Citation
Immunity, 2015, 43 (3), pp.475-487
ISSN
1074-7613
Publisher
Elsevier
Start Page
475
End Page
487
Journal / Book Title
Immunity
Volume
43
Issue
3
Copyright Statement
© 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Identifier
PII: S1074-7613(15)00310-6
Subjects
IL-17
Regnase-1
autoimmunity
fungal immunity
negative regulation
signal transduction
Acute-Phase Proteins
Adaptor Proteins, Signal Transducing
Animals
Candida albicans
Candidiasis
Cell Line
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental
Female
HEK293 Cells
Host-Pathogen Interactions
Humans
Immunoblotting
Inflammation
Interleukin-17
Interleukin-6
Lipocalin-2
Lipocalins
Male
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins
Oncogene Proteins
Pneumonia
Receptors, Interleukin-17
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleases
Signal Transduction
Publication Status
Published