Abstract
Regnase-1 is an RNA-binding protein with ribonuclease activities, and once induced it controls diverse immune responses by degrading mRNAs that encode inflammatory cytokines and costimulatory molecules, thus exerting potent anti-inflammatory functions. However, Regnase-1 is extremely sensitive to degradation by proteases and therefore short-lived. Here, we constructed a mutant Regnase-1 that is resistant to degradation and expressed this mutant in vivo as a transgene specifically in T cells. We found that the mutant Regnase-1 transgenic mice exhibited profound lymphopenia in the periphery despite grossly normal spleen and lymph nodes, and spontaneously accepted skin allografts without any treatment. Mechanistic studies showed that in the transgenic mice thymic T cell development was disrupted, such that most of the developing thymocytes were arrested at the double positive stage, with few mature CD4+ and CD8+ T cells in the thymus and periphery. Our findings suggest that interfering with the dynamic Regnase-1 expression in T cells disrupts T cell development and functions and further studies are warranted to uncover the mechanisms involved.
Highlights
IntroductionRegnase-1 ( known as Zc3h12a and MCPIP1) is an RNase that is widely expressed in various immune cells, including macrophages, B cells and T cells [1]
Regnase-1 is an RNase that is widely expressed in various immune cells, including macrophages, B cells and T cells [1]
We further investigated the influence of mutant Regnase-1 on thymocyte apoptosis
Summary
Regnase-1 ( known as Zc3h12a and MCPIP1) is an RNase that is widely expressed in various immune cells, including macrophages, B cells and T cells [1]. Most of the mRNAs encoding cytokines and costimulatory molecules are short lived, which constitutes an important negative regulatory mechanism of immune responses [2, 3]. Regnase-1 serves as an anti-inflammatory role by breaking down mRNAs that encode potent inflammatory cytokines, and inhibits immune activation. As the immune responses are often tightly controlled in order to prevent collateral damage due to sustained immune responses [6, 7], Regnase-1 acts as an important feedback regulatory mechanism to negatively control immune responses
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