MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.
MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.
复制标题
DOI：
10.1016/j.immuni.2015.07.021
复制
发表时间：
2015-09-15
期刊：
影响因子：
32.4
通讯作者：
Gaffen SL
中科院分区：
文献类型：
--
作者：
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
白细胞介素-17（IL-17）诱导自身免疫和感染的病理;因此，该途径的约束是其调节的重要组成部分。我们证明了信号中间体MCPIP 1（也称为Regnase-1，由Zc 3 h12 a编码）是IL-17受体信号转导的反馈抑制剂。MCPIP 1敲低增强了IL-17介导的信号传导，需要MCPIP 1的核糖核酸内切酶而不是去泛素化酶结构域。MCPIP 1单倍不足小鼠表现出对播散性白色念珠菌感染的抵抗力增强，这在Il 17 ra −/−背景下逆转。相反，Zc 3 h12 a +/−小鼠的IL-17依赖性病理在EAE和肺部炎症中均加重。MCPIP 1直接降解IL-6 mRNA，但仅适度下调IL-6启动子。然而，MCPIP 1通过调节编码IκB β转录因子的Nfkbiz的mRNA稳定性来强烈抑制Lcn 2启动子。出乎意料的是，MCPIP 1降解Il 17 ra和Il 17 rc mRNA，不依赖于3' UTR。MCPIP 1对IL-6、IκB β和可能的IL-17 R亚基的累积影响导致IL-17信号传导的生物学相关抑制。
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.