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

Abhishek V. Garg; Nilesh Amatya; Kong Chen; J. Agustin Cruz; Prerna Grover; Natasha Whibley; Heather R. Conti; Gerard Hernandez Mir; Tatiana Sirakova; Erin C. Childs; Thomas E. Smithgall; Partha S. Biswas; Jay K. Kolls; Mandy J. McGeachy; Pappachan E. Kolattukudy; Sarah L. Gaffen

doi:10.1016/j.immuni.2015.07.021

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

Abhishek V. Garg
, Nilesh Amatya
, Kong Chen
, J. Agustin Cruz
, Prerna Grover
, Natasha Whibley
, Heather R. Conti
, Gerard Hernandez Mir
, Tatiana Sirakova
, Erin C. Childs
, Thomas E. Smithgall
, Partha S. Biswas
, Jay K. Kolls
, Mandy J. McGeachy
, Pappachan E. Kolattukudy
, Sarah L. Gaffen

Microbiology and Immunology

University of Pittsburgh
University of Central Florida

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

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.

Original language	English
Article number	3141
Pages (from-to)	475-487
Number of pages	13
Journal	Immunity
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2015.07.021
State	Published - Sep 15 2015

Keywords

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

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10.1016/j.immuni.2015.07.021

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Garg, A. V., Amatya, N., Chen, K., Cruz, J. A., Grover, P., Whibley, N., Conti, H. R., Hernandez Mir, G., Sirakova, T., Childs, E. C., Smithgall, T. E., Biswas, P. S., Kolls, J. K., McGeachy, M. J., Kolattukudy, P. E., & Gaffen, S. L. (2015). MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity, 43(3), 475-487. Article 3141. https://doi.org/10.1016/j.immuni.2015.07.021

@article{f62b8e4476934b51b60d55a11e617469,

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.",

keywords = "Autoimmunity, Fungal immunity, IL-17, Negative regulation, Regnase-1, Signal transduction",

author = "Garg, \{Abhishek V.\} and Nilesh Amatya and Kong Chen and Cruz, \{J. Agustin\} and Prerna Grover and Natasha Whibley and Conti, \{Heather R.\} and \{Hernandez Mir\}, Gerard and Tatiana Sirakova and Childs, \{Erin C.\} and Smithgall, \{Thomas E.\} and Biswas, \{Partha S.\} and Kolls, \{Jay K.\} and McGeachy, \{Mandy J.\} and Kolattukudy, \{Pappachan E.\} and Gaffen, \{Sarah L.\}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = sep,

day = "15",

doi = "10.1016/j.immuni.2015.07.021",

language = "English",

volume = "43",

pages = "475--487",

journal = "Immunity",

issn = "1074-7613",

number = "3",

}

Garg, AV, Amatya, N, Chen, K, Cruz, JA, Grover, P, Whibley, N, Conti, HR, Hernandez Mir, G, Sirakova, T, Childs, EC, Smithgall, TE, Biswas, PS, Kolls, JK, McGeachy, MJ, Kolattukudy, PE & Gaffen, SL 2015, 'MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation', Immunity, vol. 43, no. 3, 3141, pp. 475-487. https://doi.org/10.1016/j.immuni.2015.07.021

TY - JOUR

T1 - MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation

AU - Garg, Abhishek V.

AU - Amatya, Nilesh

AU - Chen, Kong

AU - Cruz, J. Agustin

AU - Grover, Prerna

AU - Whibley, Natasha

AU - Conti, Heather R.

AU - Hernandez Mir, Gerard

AU - Sirakova, Tatiana

AU - Childs, Erin C.

AU - Smithgall, Thomas E.

AU - Biswas, Partha S.

AU - Kolls, Jay K.

AU - McGeachy, Mandy J.

AU - Kolattukudy, Pappachan E.

AU - Gaffen, Sarah L.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - 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.

AB - 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.

KW - Autoimmunity

KW - Fungal immunity

KW - IL-17

KW - Negative regulation

KW - Regnase-1

KW - Signal transduction

UR - https://www.scopus.com/pages/publications/84941732348

U2 - 10.1016/j.immuni.2015.07.021

DO - 10.1016/j.immuni.2015.07.021

M3 - Article

C2 - 26320658

AN - SCOPUS:84941732348

SN - 1074-7613

VL - 43

SP - 475

EP - 487

JO - Immunity

JF - Immunity

IS - 3

M1 - 3141

ER -

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

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Keywords

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