The CCR4-NOT Complex Maintains Liver Homeostasis Through MRNA Deadenylation

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2020 Apr 3

PMID 32238456

Citations 16

Authors

Akinori Takahashi

Toru Suzuki

Shou Soeda

Shohei Takaoka

Shungo Kobori

Tomokazu Yamaguchi

Haytham Mohamed Aly Mohamed

Akiko Yanagiya

Takaya Abe

Mayo Shigeta

Yasuhide Furuta

Keiji Kuba

Tadashi Yamamoto

Affiliations

Soon will be listed here.

Abstract

The biological significance of deadenylation in global gene expression is not fully understood. Here, we show that the CCR4-NOT deadenylase complex maintains expression of mRNAs, such as those encoding transcription factors, cell cycle regulators, DNA damage response-related proteins, and metabolic enzymes, at appropriate levels in the liver. Liver-specific disruption of , encoding a scaffold subunit of the CCR4-NOT complex, leads to increased levels of mRNAs for transcription factors, cell cycle regulators, and DNA damage response-related proteins because of reduced deadenylation and stabilization of these mRNAs. CNOT1 suppression also results in an increase of immature, unspliced mRNAs (pre-mRNAs) for apoptosis-related and inflammation-related genes and promotes RNA polymerase II loading on their promoter regions. In contrast, mRNAs encoding metabolic enzymes become less abundant, concomitant with decreased levels of these pre-mRNAs. Lethal hepatitis develops concomitantly with abnormal mRNA expression. Mechanistically, the CCR4-NOT complex targets and destabilizes mRNAs mainly through its association with Argonaute 2 (AGO2) and butyrate response factor 1 (BRF1) in the liver. Therefore, the CCR4-NOT complex contributes to liver homeostasis by modulating the liver transcriptome through mRNA deadenylation.

Citing Articles

Tristetraprolin Family Members and Processing Bodies: A Complex Regulatory Network Involved in Fatty Liver Disease, Viral Hepatitis and Hepatocellular Carcinoma.

Gellee N, Legrand N, Jouve M, Devaux P, Dubuquoy L, Sobolewski C Cancers (Basel). 2025; 17(3).

PMID: 39941720 PMC: 11815756. DOI: 10.3390/cancers17030348.

Disrupted Post-Transcriptional Regulation of Gene Expression as a Hallmark of Fatty Liver Progression.

Takaoka S, Jaso-Vera M, Ruan X Int J Mol Sci. 2024; 25(20).

PMID: 39456836 PMC: 11507451. DOI: 10.3390/ijms252011054.

Nuclear mRNA decay: regulatory networks that control gene expression.

Rambout X, Maquat L Nat Rev Genet. 2024; 25(10):679-697.

PMID: 38637632 PMC: 11408106. DOI: 10.1038/s41576-024-00712-2.

Establishment and characterization of turtle liver organoids provides a potential model to decode their unique adaptations.

Zdyrski C, Gabriel V, Gessler T, Ralston A, Sifuentes-Romero I, Kundu D Commun Biol. 2024; 7(1):218.

PMID: 38388772 PMC: 10883927. DOI: 10.1038/s42003-024-05818-1.

Comprehensive analysis of m6A reader YTHDF2 prognosis, immune infiltration, and related regulatory networks in hepatocellular carcinoma.

Wang H, Cai H, Li L Heliyon. 2024; 10(1):e23204.

PMID: 38163150 PMC: 10756983. DOI: 10.1016/j.heliyon.2023.e23204.

References

Li Q, Brass A, Ng A, Hu Z, Xavier R, Liang T . A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc Natl Acad Sci U S A. 2009; 106(38):16410-5. PMC: 2752535. DOI: 10.1073/pnas.0907439106. View

Inoue T, Morita M, Hijikata A, Fukuda-Yuzawa Y, Adachi S, Isono K . CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. J Exp Med. 2015; 212(9):1465-79. PMC: 4548056. DOI: 10.1084/jem.20150384. View

Martinez-Jimenez C, Kyrmizi I, Cardot P, Gonzalez F, Talianidis I . Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol. 2009; 30(3):565-77. PMC: 2812226. DOI: 10.1128/MCB.00927-09. View

Yamaguchi T, Suzuki T, Sato T, Takahashi A, Watanabe H, Kadowaki A . The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function. Sci Signal. 2018; 11(516). DOI: 10.1126/scisignal.aan3638. View

Yagi T, Tokunaga T, Furuta Y, Nada S, Yoshida M, Tsukada T . A novel ES cell line, TT2, with high germline-differentiating potency. Anal Biochem. 1993; 214(1):70-6. DOI: 10.1006/abio.1993.1458. View

Suzuki T, Kikuguchi C, Sharma S, Sasaki T, Tokumasu M, Adachi S . CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins. Sci Rep. 2015; 5:14779. PMC: 4594005. DOI: 10.1038/srep14779. View

Desvergne B, Michalik L, Wahli W . Transcriptional regulation of metabolism. Physiol Rev. 2006; 86(2):465-514. DOI: 10.1152/physrev.00025.2005. View

Mugridge J, Coller J, Gross J . Structural and molecular mechanisms for the control of eukaryotic 5'-3' mRNA decay. Nat Struct Mol Biol. 2018; 25(12):1077-1085. DOI: 10.1038/s41594-018-0164-z. View

Nousch M, Techritz N, Hampel D, Millonigg S, Eckmann C . The Ccr4-Not deadenylase complex constitutes the main poly(A) removal activity in C. elegans. J Cell Sci. 2013; 126(Pt 18):4274-85. DOI: 10.1242/jcs.132936. View

10.

Schuler M, Dierich A, Chambon P, Metzger D . Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse. Genesis. 2004; 39(3):167-72. DOI: 10.1002/gene.20039. View

11.

Takahashi A, Takaoka S, Kobori S, Yamaguchi T, Ferwati S, Kuba K . The CCR4-NOT Deadenylase Complex Maintains Adipocyte Identity. Int J Mol Sci. 2019; 20(21). PMC: 6862216. DOI: 10.3390/ijms20215274. View

12.

Tsai W, Hsu S, Hsu C, Lai T, Chen S, Shen R . MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012; 122(8):2884-97. PMC: 3408747. DOI: 10.1172/JCI63455. View

13.

Gaidatzis D, Burger L, Florescu M, Stadler M . Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation. Nat Biotechnol. 2015; 33(7):722-9. DOI: 10.1038/nbt.3269. View

14.

Miller J, Reese J . Ccr4-Not complex: the control freak of eukaryotic cells. Crit Rev Biochem Mol Biol. 2012; 47(4):315-33. PMC: 3376659. DOI: 10.3109/10409238.2012.667214. View

15.

Luna J, Barajas J, Teng K, Sun H, Moore M, Rice C . Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer. Mol Cell. 2017; 67(3):400-410.e7. PMC: 5603316. DOI: 10.1016/j.molcel.2017.06.025. View

16.

Mittal S, Aslam A, Doidge R, Medica R, Winkler G . The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4-Not complex contribute to the prevention of cell death and senescence. Mol Biol Cell. 2011; 22(6):748-58. PMC: 3057700. DOI: 10.1091/mbc.E10-11-0898. View

17.

Tarling E, Clifford B, Cheng J, Morand P, Cheng A, Lester E . RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest. 2017; 127(10):3741-3754. PMC: 5617661. DOI: 10.1172/JCI94029. View

18.

Edri S, Tuller T . Quantifying the effect of ribosomal density on mRNA stability. PLoS One. 2014; 9(7):e102308. PMC: 4096589. DOI: 10.1371/journal.pone.0102308. View

19.

Boland A, Chen Y, Raisch T, Jonas S, Kuzuoglu-Ozturk D, Wohlbold L . Structure and assembly of the NOT module of the human CCR4-NOT complex. Nat Struct Mol Biol. 2013; 20(11):1289-97. DOI: 10.1038/nsmb.2681. View

20.

Yamaji M, Jishage M, Meyer C, Suryawanshi H, Der E, Yamaji M . DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs. Nature. 2017; 543(7646):568-572. PMC: 5488729. DOI: 10.1038/nature21690. View