title: MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.
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.
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Abhishek V
authors: AV
authors: Garg
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Nilesh
authors: N
authors: Amatya
authors: Department of Pediatrics & Immunology, Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors: Kong
authors: K
authors: Chen
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: J Agustin
authors: JA
authors: Cruz
authors: Department of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Prerna
authors: P
authors: Grover
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Natasha
authors: N
authors: Whibley
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Heather R
authors: HR
authors: Conti
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Gerard
authors: G
authors: Hernandez Mir
authors: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors: Tatiana
authors: T
authors: Sirakova
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Erin C
authors: EC
authors: Childs
authors: Department of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Thomas E
authors: TE
authors: Smithgall
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Partha S
authors: PS
authors: Biswas
authors: Department of Pediatrics & Immunology, Richard King Mellon Institute for Pediatric Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors: Jay K
authors: JK
authors: Kolls
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Mandy J
authors: MJ
authors: McGeachy
authors: Department of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Pappachan E
authors: PE
authors: Kolattukudy
authors: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: sarah.gaffen@pitt.edu.
authors: Sarah L
authors: SL
authors: Gaffen
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000276:immunology / Q000502:physiology; D002177:Candidiasis / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D002460:Cell Line; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D015850:Interleukin-6; D000071068:Lipocalin-2; D054834:Lipocalins; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D053722:Receptors, Interleukin-17; C071332:Lcn2 protein, mouse; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse
keywords: IL-17; Regnase-1; autoimmunity; fungal immunity; negative regulation; signal transduction