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• W2899471154 abstract "News & Views2 November 2018free access Hepatic ERAD takes control of the organism Lena-Sophie Dreher Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany Search for more papers by this author Thorsten Hoppe [email protected] orcid.org/0000-0002-4734-9352 Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany Search for more papers by this author Lena-Sophie Dreher Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany Search for more papers by this author Thorsten Hoppe [email protected] orcid.org/0000-0002-4734-9352 Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany Search for more papers by this author Author Information Lena-Sophie Dreher1 and Thorsten Hoppe1 1Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany EMBO J (2018)37:e100676https://doi.org/10.15252/embj.2018100676 See also: J Wei et al (November 2018) and A Bhattacharya et al (November 2018) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Upregulation of Endoplasmic Reticulum-Associated Degradation (ERAD) in the liver upon feeding and organismal growth aggravates proteasomal turnover of the transcription factor CREBH and decreases the expression of its target gene, the hepatokine FGF21. Wei et al and Bhattacharya et al describe the systemic coordination of energy metabolism and organismal physiology mediated by hepatic-specific ERAD function. ERAD is a key quality control mechanism in the cell that recognizes misfolded proteins in the endoplasmic reticulum (ER). These proteins are retro-translocated for ubiquitylation and proteasomal degradation into the cytosol. The best characterized E3 ligase responsible for the ubiquitylation of luminal and membrane-bound proteins is Hrd-1 coupled to its regulatory adaptor Sel-1L (Wu & Rapoport, 2018). While the molecular basis of ERAD function has been extensively studied in Saccharomyces cerevisiae and mammalian cells, its physiological relevance in multicellular organisms is currently poorly explored. Upon ER stress, the ERAD machinery is transcriptionally upregulated by the corresponding unfolded protein response pathway (UPRER). Conversely, recent findings have described a role of ERAD in feedback regulation of the UPRER. For example, Ire-1α, one of the three ER-associated stress sensors, is degraded via ERAD to downregulate stress response. Since the whole-body knockout of Hrd-1 is lethal, little information has been gathered on its substrates. Therefore, targeted depletion of ERAD opened up a new route to study Hrd-1-dependent degradation pathways. Recent work on tissue-specific regulation mechanisms has already identified additional ERAD substrates important for UPRER, such as the antioxidant transcription factor Nrf-2 in hepatocytes and the ER luminal lectin Os-9 and the lipoprotein lipase Lpl in adipocytes (Qi et al, 2017). Wei et al and Bhattacharya et al characterized liver-specific Hrd-1 and Sel-1L knockout mice and identified a key role for ERAD in energy metabolism. The knockout mice displayed growth retardation, female infertility, improved insulin sensitivity, and reduced body weight upon feeding with high-fat diet. These phenotypes resembled those induced by overexpression of fibroblast growth factor 21 (FGF21). Strikingly, serum and hepatic levels of FGF21 were upregulated in Hrd-1 and Sel-1L knockout mice suggesting a direct regulation mechanism (Bookout et al, 2013; Bhattacharya et al, 2018; Wei et al, 2018). FGF21 is a hepatokine, which is involved in the regulation of carbohydrate and fatty acid metabolism in the liver (Fon Tacer et al, 2010). Prolonged fasting strongly induces hepatic expression of endocrine FGF21 in mice, which can induce browning of white adipose tissue (Shan et al, 2018). Interestingly, animal models of type 2 diabetes and obesity treated with FGF21 displayed reduced body weight, fat mass, and hepatic triglyceride content, and displayed improved glucose tolerance and insulin sensitivity (Nygaard et al, 2018; Shan et al, 2018). According to its hepatokine function, FGF21 expression is tightly regulated by various transcription factors. Upon ER stress, FGF21 levels are increased through ER-resident transcription factors Atf-4, Chop, and Xbp-1s, demonstrating a close interplay between ER homeostasis and FGF21 regulation. Atf-4 further activates FGF21 expression upon autophagy deficiency in muscle cells or food deprivation. Fasting-induced FGF21 expression is regulated by transcription factor cyclic adenosine monophosphate-responsive element-binding protein H (CREBH) and peroxisome proliferator-activated receptor alpha (Pparα) (Nakagawa & Shimano, 2018). In agreement with the phenotypic correlation, the metabolic phenotypes in both liver-specific Hrd-1 and Sel-1L knockout mice were in part related to FGF21 levels. In fact, proteomics and RNA-sequencing analyses of liver extracts from these knockout mice identified the transcription factor CREBH as a potential target of ERAD in the liver. CREBH is anchored to the ER membrane and transported along the secretory pathway to the Golgi apparatus where it is cleaved off the membrane by site-1- and site-2-specific proteases, which are also involved in cholesterol metabolism. The soluble, active form of CREBH (CREBH-N) subsequently translocates to the nucleus where it is thought to form a complex with Pparα to induce FGF21 expression (Brown & Goldstein, 1999; Wang et al, 2016). Biochemical experiments showed that CREBH directly interacts with the ERAD machinery for ubiquitin-dependent degradation initiated by the E3 ligase Hrd-1 (Bhattacharya et al, 2018; Wei et al, 2018). While ERAD substrates are usually polyubiquitylated via lysine residues K11 and/or K48 (Locke et al, 2014), Wei et al suggested that CREBH is modified with K27-linked ubiquitin chains (Wei et al, 2018). This finding raises the question why CREBH ubiquitylation is mediated via a non-canonical linkage-type: Is K27-linked ubiquitin chain topology regulated by fasting signals? The degradation of CREBH plays a crucial role in the feeding and fasting cycle as well as during growth (Fig 1). As a function of organismal energy metabolism, the Hrd-1-Sel-1L complex is upregulated in the liver, which leads to the degradation of CREBH and reduction of FGF21 level. Otherwise, defects in ERAD result in increased CREBH level and FGF21 overexpression. Considering the liver-specific role of ERAD, it will be interesting to further address how Hrd-1 and Sel-1L are upregulated upon metabolic changes and which factors are involved in the feeding response. A rather intriguing possibility is that ERAD might be directly regulated by changes in food composition. Taken together, Wei et al and Bhattacharya et al identified a systemic role of ERAD by regulating the abundance of the hepatokine FGF21, which nicely demonstrates the tremendous impact of tissue-specific regulation mechanisms for organismal energy metabolism and physiology. Future studies on similar tissue-specific ERAD pathways will shed light on its physiological relevance related to metabolic and aging-associated diseases. Figure 1. Degradation of CREBH through ERAD regulates hepatic FGF21 levelDuring fasting, CREBH is transported to the Golgi where it is subsequently cleaved by the site-specific proteases, site-1 protease (S1P) and site-2 protease (S2P). CREBH-N, the active form of CREBH, translocates to the nucleus where it forms a complex with Pparα to activate FGF21 expression and further regulate metabolism. During feeding, the hepatic ERAD machinery is upregulated and degrades the transcription factor CREBH resulting in downregulation of FGF21. Download figure Download PowerPoint References Bhattacharya A, Sun S, Wang H, Liu M, Long Q, Yin L, Kersten S, Zhang K, Qi L (2018) Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. EMBO J 37: e99277Wiley Online LibraryPubMedWeb of Science®Google Scholar Bookout AL, De Groot MHM, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK, Takahashi JS, Mangelsdorf DJ, Kliewer SA (2013) FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 19: 1147–1152CrossrefCASPubMedWeb of Science®Google Scholar Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96: 11041–11048CrossrefCASPubMedWeb of Science®Google Scholar Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Goetz R, Mohammadi M, Kuro-o M, Mangelsdorf DJ, Kliewer SA (2010) Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24: 2050–2064CrossrefCASPubMedWeb of Science®Google Scholar Locke M, Toth JI, Petroski MD (2014) K11- and K48-linked ubiquitin chains interact with p97 during endoplasmic reticulum-associated degradation. Biochem J 459: 205–216CrossrefCASPubMedWeb of Science®Google Scholar Nakagawa Y, Shimano H (2018) CREBH regulates systemic glucose and lipid metabolism. Int J Mol Sci 19: 1–15CrossrefWeb of Science®Google Scholar Nygaard EB, Ørskov C, Almdal T, Henrik V, Andersen B (2018) Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects. J Endocrinol 239: 73–80CrossrefCASPubMedGoogle Scholar Qi L, Tsai B, Arvan P (2017) New insights into the physiological role of endoplasmic reticulum-associated degradation. Trends Cell Biol 27: 430–440CrossrefCASPubMedWeb of Science®Google Scholar Shan Z, Alvarez-Sola G, Uriarte I, Arechederra M, Fernández-Barrena MG, Berasain C, Ju C, Avila MA (2018) Fibroblast growth factors 19 and 21 in acute liver damage. Ann Transl Med 6: 257CrossrefPubMedWeb of Science®Google Scholar Wang M, Zhao S, Tan M (2016) BZIP transmembrane transcription factor CREBH: potential role in non-alcoholic fatty liverdisease (Review). Mol Med Rep 13: 1455–1462CrossrefCASPubMedWeb of Science®Google Scholar Wei J, Chen L, Li F, Yuan Y, Wang Y, Xia W, Zhang Y, Xu Y, Yang Z, Gao B, Jin C, Melo-cardenas J, Green RM, Pan H, Wang J, He F, Zhang K, Fang D (2018) HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. EMBO J 37: e98942Wiley Online LibraryPubMedWeb of Science®Google Scholar Wu X, Rapoport TA (2018) Mechanistic insights into ER-associated protein degradation. Curr Opin Cell Biol 53: 22–28CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 37,Issue 22,15 November 2018Caption: Severe fragmentation or dilation of the central lymph vessel (lacteal, LYVE‐1, cyan) in intestinal villi after deletion of the junctional adhesion molecule VE‐cadherin in lymphatic endothelial cells. Immunostaining of the endothelial surface protein PECAM‐1 (green) identifies blood vessels, smooth muscle actin (red) smooth muscle cells and E‐cadherin (blue) enterocytes. By René Hägerling, Esther Hoppe, Cathrin Dierkes, Friedemann Kiefer and colleagues: Distinct roles of VE‐cadherin for development and maintenance of specific lymph vessel beds. Scientific image by Esther Hoppe and Friedemann Kiefer, Max Planck Institute for Molecular Biomedicine/ European Institute for Molecular Imaging, Münster, Germany. 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