2. Academic Validation
  3. MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation

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

  • Immunity. 2015 Sep 15;43(3):475-87. doi: 10.1016/j.immuni.2015.07.021.
Abhishek V Garg 1,  Nilesh Amatya 1,  Kong Chen 2,  J Agustin Cruz 1,  Prerna Grover 3,  Natasha Whibley 1,  Heather R Conti 1,  Gerard Hernandez Mir 1,  Tatiana Sirakova 4,  Erin C Childs 1,  Thomas E Smithgall 3,  Partha S Biswas 1,  Jay K Kolls 2,  Mandy J McGeachy 1,  Pappachan E Kolattukudy 3,  Sarah L Gaffen 5
Affiliations

Affiliations

  • 1 Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 2 Department of Pediatrics & Immunology, Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
  • 3 Department of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 4 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
  • 5 Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: sarah.gaffen@pitt.edu.
PMID: 26320658 DOI: 10.1016/j.immuni.2015.07.021
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.

Keywords

IL-17; Regnase-1; autoimmunity; fungal immunity; negative regulation; signal transduction.

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