title: Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation.
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 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.
authors.affiliation: Laboratory of Host Defense, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Uehata
authors.forename: Hidenori
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Alexis
authors.initials: A
authors.lastname: Vandenbon
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Matsushita
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez-Cuellar
authors.forename: Kanako
authors.initials: K
authors.lastname: Kuniyoshi
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D020169:Caspases / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D053278:OX40 Ligand; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics
chemical_list: D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053278:OX40 Ligand; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein