Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation

被引：287

作者：

Uehata, Takuya ^{[1
,4
]}

Iwasaki, Hidenori ^{[1
,5
]}

Vandenbon, Alexis ^{[2
]}

Matsushita, Kazufumi ^{[1
]}

Hernandez-Cuellar, Eduardo ^{[1
]}

Kuniyoshi, Kanako ^{[1
,3
]}

Satoh, Takashi ^{[1
,3
]}

Mino, Takashi ^{[6
]}

Suzuki, Yutaka ^{[8
]}

Standley, Daron M. ^{[2
]}

Tsujimura, Tohru ^{[9
]}

Rakugi, Hiromi ^{[4
]}

Isaka, Yoshitaka ^{[4
]}

Takeuchi, Osamu ^{[1
,6
,7
]}

Akira, Shizuo ^{[1
,3
]}

机构：

[1] Osaka Univ, Lab Host Def, Suita, Osaka 5650871, Japan

[2] Osaka Univ, WPI Immunol Frontier Res Ctr IFReC, Lab Syst Immunol, Suita, Osaka 5650871, Japan

[3] Osaka Univ, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan

[4] Osaka Univ, Grad Sch Med, Dept Geriatr Med & Nephrol, Suita, Osaka 5650871, Japan

[5] Japan Tobacco, Cent Pharmaceut Res Inst, Takatsuki, Osaka 5691125, Japan

[6] Kyoto Univ, Inst Virus Res, Lab Infect & Prevent, Sakyo Ku, Kyoto 6068507, Japan

[7] JST, CREST, Sakyo Ku, Kyoto 6068507, Japan

[8] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Lab Funct Genom, Kashiwa, Chiba 2778562, Japan

[9] Hyogo Coll Med, Dept Pathol, Nishinomiya, Hyogo 6638501, Japan

来源：

CELL | 2013年 / 153卷 / 05期

基金：

日本学术振兴会;

关键词：

MESSENGER-RNA; TRANSCRIPTION FACTORS; C-REL; ROLES; GENES; MALT1; MICRORNAS; STABILITY; ALPHA;

D O I：

10.1016/j.cell.2013.04.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 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.

引用

页码：1036 / 1049

页数：14

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