The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function

被引：68

作者：

Yamaguchi, Tomokazu ^{[1
]}

Suzuki, Takashi ^{[1
]}

Sato, Teruki ^{[2
]}

Takahashi, Akinori ^{[3
]}

Watanabe, Hiroyuki ^{[2
]}

Kadowaki, Ayumi ^{[1
]}

Natsui, Miyuki ^{[1
]}

Inagaki, Hideaki ^{[4
]}

Arakawa, Satoko ^{[5
]}

Nakaoka, Shinji ^{[6
,7
]}

Koizumi, Yukio ^{[1
]}

Seki, Shinsuke ^{[4
]}

Adachi, Shungo ^{[8
]}

Fukao, Akira ^{[9
]}

Fujiwara, Toshinobu ^{[9
]}

Natsume, Tohru ^{[8
]}

Kimura, Akinori ^{[10
]}

Komatsu, Masaaki ^{[11
]}

Shimizu, Shigeomi

Ito, Hiroshi ^{[2
]}

Suzuki, Yutaka ^{[12
]}

Penninger, Josef M. ^{[13
]}

Yamamoto, Tadashi ^{[3
]}

Imai, Yumiko

Kuba, Keiji ^{[1
,14
]}

机构：

[1] Akita Univ, Grad Sch Med, Dept Biochem & Metab Sci, 1-1-1 Hondo, Akita 0108543, Japan

[2] Akita Univ, Grad Sch Med, Dept Cardiovasc & Resp Med, Akita 0108543, Japan

[3] Grad Univ, Okinawa Inst Sci & Technol, Okinawa 9040495, Japan

[4] Akita Univ, Biosci Educ & Res Support Ctr, Akita 0108543, Japan

[5] Tokyo Med & Dent Univ, Med Res Inst, Dept Pathol Cell Biol, Tokyo 1138510, Japan

[6] Univ Tokyo, Inst Ind Sci, Tokyo 1538505, Japan

[7] Natl Inst Biomed Innovat Hlth & Nutr, Lab Regulat Intractable Infect Dis, Ibaraki, Osaka 5670085, Japan

[8] Natl Inst Adv Ind Sci & Technol, Mol Profiling Res Ctr Drug Discovery, Tokyo 1350064, Japan

[9] Kindai Univ, Dept Pharm, Mol Lab Biochem, Higashiosaka, Osaka 5778502, Japan

[10] Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Pathogenesis, Tokyo 1138510, Japan

[11] Niigata Univ, Sch Med, Dept Biochem, Niigata 9518510, Japan

[12] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Chiba 2778562, Japan

[13] Austrian Acad Sci, Inst Mol Biotechnol, Campus Vienna BioCtr, A-1030 Vienna, Austria

[14] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol PRESTO, Tokyo 1020076, Japan

来源：

SCIENCE SIGNALING | 2018年 / 11卷 / 516期

基金：

日本科学技术振兴机构; 日本学术振兴会;

关键词：

QT INTERVAL DURATION; COMMON VARIANTS; MESSENGER-RNAS; AUTOPHAGY; SUPPRESSION; REGULATOR; DELETION; MODELS; APELIN; STATE;

D O I：

10.1126/scisignal.aan3638

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death-promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis.

引用

页数：12

共 46 条

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