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Hepatic Posttranscriptional Network Comprised of CCR4–NOT Deadenylase and FGF21 Maintains Systemic Metabolic Homeostasis

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Hepatic posttranscriptional network comprised of CCR4–NOT deadenylase and FGF21 maintains systemic metabolic homeostasis Masahiro Moritaa,b,c,1,2, Nadeem Siddiquid,e,1, Sakie Katsumuraa,b, Christopher Rouyad,e, Ola Larssonf, Takeshi Nagashimag, Bahareh Hekmatnejadh,i, Akinori Takahashij, Hiroshi Kiyonarik, Mengwei Zanga,b, René St-Arnaudh,i, Yuichi Oikel, Vincent Giguèred,e,m, Ivan Topisirovicd,m,n, Mariko Okada-Hatakeyamag,o, Tadashi Yamamotoj,2, and Nahum Sonenbergd,e,2 aDepartment of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; bBarshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; cInstitute of Resource Development and Analysis, Kumamoto University, 860-0811 Kumamoto, Japan; dDepartment of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; eGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; fDepartment of Oncology-Pathology, Scilifelab, Karolinska Institutet, SE-171 76 Stockholm, Sweden; gLaboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Kanagawa, Japan; hResearch Centre, Shriners Hospital for Children–Canada, Montreal, QC H4A 0A9, Canada; iDepartment of Human Genetics, McGill University, Montreal, QC H3A 2T5, Canada; jCell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, 904-0495 Okinawa, Japan; kLaboratories for Animal Resource Development and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047 Hyogo, Japan; lDepartment of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 860-8556 Kumamoto, Japan; mGerald Bronfman Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada; nLady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; and oLaboratory of Cell Systems, Institute for Protein Research, Osaka University, Suita, 565-0871 Osaka, Japan Contributed by Nahum Sonenberg, February 24, 2019 (sent for review September 17, 2018; reviewed by Jack D. Keene and David J. Mangelsdorf) Whole-body metabolic homeostasis is tightly controlled by hormone- CCR4–NOT-dependent deadenylation by RBPs and the miRISC like factors with systemic or paracrine effects that are derived (18). However, the composition and function of CCR4–NOT from nonendocrine organs, including adipose tissue (adipokines) containing messenger ribonucleoprotein (mRNP) complexes in and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a physiological and pathological states remain obscure (19). MEDICAL SCIENCES hormone-like protein, which is emerging as a major regulator of The CCR4–NOT complex has been implicated in the develop- whole-body metabolism and has therapeutic potential for treating ment of metabolic diseases (20–24). These disorders, including di- metabolic syndrome. However, the mechanisms that control FGF21 abetes, steatosis, hyperlipidemia, and obesity, are major worldwide levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4–NOT deadenylase complex and RNA-binding Significance protein tristetraprolin (TTP). In response to nutrient uptake, CCR4– NOT cooperates with TTP to degrade AU-rich mRNAs that encode The mRNA poly(A) tail controls gene expression at post- pivotal metabolic regulators, including FGF21. Disruption of CCR4– transcriptional levels, including mRNA degradation and trans- NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, lation. Here, we show that a hitherto unknown hepatic increases serum FGF21 levels, which ameliorates diet-induced meta- posttranscriptional network centered on the CCR4–NOT dead- bolic disorders and enhances energy expenditure without disrupting enylase plays a seminal role in regulating FGF21 expression and bone homeostasis. Taken together, our study describes a hepatic its effects on systemic metabolism. A genome-wide search for CCR4–NOT/FGF21 axis as a hitherto unrecognized systemic regula- CNOT6L-associated mRNAs unveiled the mechanism whereby tor of metabolism and suggests that hepatic CCR4–NOT may serve CNOT6L selectively degrades a subset of mRNAs encoding met- as a target for devising therapeutic strategies in metabolic syndrome abolic factors, including FGF21. Disruption of CCR4–NOT dead- and related morbidities. enylase activity, by targeting its catalytic subunit CNOT6L, leads to an increase in FGF21 levels, which is paralleled by a dramatic CCR4–NOT | deadenylase | FGF21 | hepatokine | metabolic syndrome improvement of metabolic syndrome. Overall, our findings describe a new paradigm in regulation of whole-body metab- he mRNA poly (A) tail plays an essential role in post- olism, whereby a hepatic posttranscriptional network governs Ttranscriptional regulation of gene expression by affecting systemic metabolic regulation via FGF21. mRNA decay and translation (1–3). Deadenylation is the rate-limiting step in mRNA degradation that, together with transcription, de- Author contributions: M.M., N. Siddiqui, T.Y., and N. Sonenberg designed research; M.M., N. Siddiqui, S.K., C.R., B.H., A.T., and H.K. performed research; M.M., O.L., H.K., M.Z., termines steady-state mRNA levels (4). mRNA deadenylation is R.S.-A., Y.O., V.G., and M.O.-H. contributed new reagents/analytic tools; M.M., O.L., primarily catalyzed by the CCR4–NOT complex, a multisubunit T.N., and B.H. analyzed data; and M.M., N. Siddiqui, S.K., C.R., O.L., I.T., M.O.-H., T.Y., protein machinery composed of the CCR4 (CNOT6L/CNOT6) and N. Sonenberg wrote the paper. deadenylase, the CNOT1 scaffold protein, and several regu- Reviewers: J.D.K., Duke University; and D.J.M., The University of Texas Southwestern latory proteins (CNOT2–CNOT11) (5–7). Medical Center. Direct recruitment of the CCR4–NOT complex to target The authors declare no conflict of interest. mRNAs destined for deadenylation and decay is mediated by sev- Published under the PNAS license. eral RNA-binding proteins (RBPs), including tristetraprolin (TTP), Data deposition: The data reported in this paper have been deposited in the Gene Ex- – pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. Nanos2, and Roquin (8 13). In addition, posttranscriptional si- GSE62365). – lencing by miRNAs occurs through association of the CCR4 NOT 1M.M. and N. Siddiqui contributed equally to this work. complex with the miRNA-induced silencing complex (miRISC) 2 To whom correspondence may be addressed. Email: [email protected], tadashi. (14–16). The selectivity of mRNA deadenylation is controlled by [email protected], or [email protected]. – cis-acting mRNA elements to which CCR4 NOT-associated RBPs This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and miRISC bind (17, 18). Previous structural and biochemi- 1073/pnas.1816023116/-/DCSupplemental. cal studies have provided mechanistic models for the selective Published online March 29, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1816023116 PNAS | April 16, 2019 | vol. 116 | no. 16 | 7973–7981 Downloaded by guest on September 27, 2021 health problems causally associated with dysregulation of meta- the stability of mRNAs that contain AREs and are enriched in bolic homeostasis. Whole-body metabolic homeostasis is closely those encoding metabolic regulators. controlled in a systemic or paracrine manner by hormone-like factors secreted from nonendocrine organs, such as adipose TTP Recruits the CCR4–NOT Complex to ARE-Containing Target mRNAs tissue (adipokines) and liver (hepatokines) (25, 26). Hormone- Destined for Degradation. Because the CCR4–NOT complex di- like proteins can either enhance [e.g., fibroblast growth factor 21 rectly interacts with the ARE-binding protein, TTP (9, 11, 12, 36), (FGF21) and leptin] or impair (e.g., resistin and selenoprotein P) we investigated whether TTP promotes CCR4–NOT-dependent energy metabolism (26, 27). However, there are no studies that degradation of endogenous target mRNAs in hepatocytes. The directly link the deadenylase activity of CCR4–NOT to hormone- CCR4–NOT complex subunits (CNOT6L, CNOT1, CNOT3, like proteins and metabolic disorders. and CNOT7) were precipitated with TTP from a hepatocyte Here, we identified target mRNAs associated with the extract (Fig. 2A). TTP directly binds to CNOT1 via a conserved CNOT6L deadenylase subunit of the CCR4–NOT complex in phenylalanine (F319) (9). Mutation of F319 to alanine (F319A) the liver by performing RNA immunoprecipitation followed by dramatically reduced the interaction between TTP and the microarray analysis (RIP-CHIP). We demonstrate that, in re- CCR4–NOT complex subunits (Fig. 2A). Moreover, CNOT6L sponse to feeding, the CCR4–NOT/TTP complex targets the coimmunoprecipitated with TTP in hepatocytes (Fig. 2B). De- AU-rich mRNA encoding the hepatokine FGF21, which allevi- pletion of TTP (Fig. 2C and SI Appendix, Fig. S3A), but not – ates diet-induced metabolic disorders (28–31). Deletion of the another CCR4 NOT-associated protein, Roquin (SI Appendix, – Cnot6l gene in mice decreased susceptibility to diet-induced Fig. S3 B D), impaired the binding of CNOT6L to ARE- metabolic disorders, such as obesity, steatosis, and hyperlipid- containing mRNAs (Fig. 2D), and enhanced their stability and emia in a deadenylase activity-dependent manner. We found that
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