Successful identification of protein playing an important role in immune response
Under the leadership of UEHATA Takuya , Researcher, and AKIRA Shizuo , Professor and Director, Immunology Frontier Research Center (IFReC), Osaka University, a group of researchers succeeded in creating mice lacking Regnase-1 in their T cells, major players in acquired immunity, and demonstrated that Regnase-1 was an important factor in controlling T cell activation. This group also demonstrated for the first time that Regnase-1 in T cells played a significant role in the development of autoimmune diseases.
Causes of autoimmune diseases are diverse and their mechanisms are not known. Generally, abnormal activation and production of autoantibodies induced by auto-reactive T cells are said to be the main cause of autoimmune diseases, but it has not been clarified why T cell activation is caused.
Previously, a group led by Professor AKIRA identified Regnase-1 as a gene in the innate immune system and demonstrated that Regnase-1 was an enzyme that broke down RNA of genes causing inflammation and reduced inflammation. (Nature, 2009) However, Regnase-1 was thought to be important only in the innate immune system.
Human autoimmune diseases and their mechanisms are diverse, but it's true that T cells, immunological play makers, play an important role. In mice lacking Regnase-1, T cells spontaneously developed autoimmune diseases, so it is obvious that Regnase-1 in human T cells play an important role in immunological response such as inflammatory suppression. Therefore, treatment strategy targeting Regnase-1 in T cells could become an effective measure against various autoimmune diseases. And regulation of Regnase-1 in T cells will increase the effectiveness of treatment. Thus, the identification of factors for controlling Regnase-1 in the future will make a great contribution to the development in this field of research and to society.
Abstract
Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 30 UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4+ T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates themRNAs
of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 30 UTRs. Interestingly,
T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation.
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To learn more about this research, please read the full research report entitled " Malt-1-induced cleavage of Regnase-1 in CD4+ Helper T cells regulates immune activation " at this page of the PNAS website.
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