Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis
Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of...
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| Published in: | The Journal of immunology (1950) Vol. 199; no. 12; p. 4066 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
15.12.2017
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| ISSN: | 1550-6606, 1550-6606 |
| Online Access: | Get more information |
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| Summary: | Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of
, but not
or
Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as
and
, via their 3' untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1550-6606 1550-6606 |
| DOI: | 10.4049/jimmunol.1701211 |