Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation.

  • Uehata T
  • Iwasaki H
  • Vandenbon A
 et al. 
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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.

Author-supplied keywords

  • Animals
  • Autoimmune Diseases
  • Autoimmune Diseases: immunology
  • Caspases
  • Caspases: metabolism
  • Humans
  • Interleukin-2
  • Interleukin-2: genetics
  • Jurkat Cells
  • Lymphocyte Activation
  • Membrane Glycoproteins
  • Membrane Glycoproteins: genetics
  • Mice
  • Neoplasm Proteins
  • Neoplasm Proteins: metabolism
  • Proto-Oncogene Proteins c-rel
  • Proto-Oncogene Proteins c-rel: genetics
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell: metabolism
  • Ribonucleases
  • Ribonucleases: metabolism
  • T-Lymphocytes, Helper-Inducer
  • T-Lymphocytes, Helper-Inducer: immunology
  • T-Lymphocytes, Helper-Inducer: metabolism
  • Tumor Necrosis Factors
  • Tumor Necrosis Factors: genetics

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  • Takuya Uehata

  • Hidenori Iwasaki

  • Alexis Vandenbon

  • Kazufumi Matsushita

  • Eduardo Hernandez-Cuellar

  • Kanako Kuniyoshi

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