[HTML][HTML] Malt1-induced cleavage of regnase-1 in CD4+ helper T cells regulates immune activation

T Uehata, H Iwasaki, A Vandenbon, K Matsushita… - Cell, 2013 - cell.com
T Uehata, H Iwasaki, A Vandenbon, K Matsushita, E Hernandez-Cuellar, K Kuniyoshi…
Cell, 2013cell.com
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 3′ 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 …
Summary
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 3′ 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 the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3′ 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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