Endoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response

Zhang, Kezhong; Shen, Xiaohua; Wu, Jun; Sakaki, Kenjiro; Saunders, Thomas L.; Rutkowski, D. Thomas; Back, Sung Hoon; Kaufman, Randal J.

doi:10.1016/j.cell.2005.11.040

Cited by 715 publications

(805 citation statements)

References 44 publications

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“…Because other UPR regulators controlled by mammalian Rip exhibit tissue-specific expression, e.g. OASIS in astrocytes (Kondo et al, 2005) and CREB-H in liver (Zhang et al, 2006), these results strongly suggest that ATF6 is indispensable to the induction of ER chaperones in response to ER stress. Furthermore, even if they were expressed in CHO cells, their contribution to the ERSE-mediated induction of ER chaperones would be marginal because CREB-H enhances UPR element-mediated transcription but not ERSE-mediated transcription (Zhang et al, 2006) and because OASIS prefers cAMP-response element to ERSE (Kondo et al, 2005).…”

Section: Discussionmentioning

confidence: 92%

“…SREBPs with a hairpin structure are responsible for cholesterol homeostasis . On the other hand, transmembrane proteins with type II topology, such as ATF6, OASIS (Kondo et al, 2005), and CREB-H (Zhang et al, 2006), are involved in the UPR where they maintain the homeostasis of the ER. Interestingly, these ER membrane-bound transcription factors are cleaved by the same two proteases localized in the Golgi apparatus, S1P and S2P, even though their activation is triggered by different stimuli .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, these ER membrane-bound transcription factors are cleaved by the same two proteases localized in the Golgi apparatus, S1P and S2P, even though their activation is triggered by different stimuli . SREBPs are translocated from the ER to the Golgi apparatus to be cleaved when cellular cholesterol levels decrease (DeBoseBoyd et al, 1999), whereas ATF6, OASIS and CREB-H relocate from the ER to the Golgi apparatus when unfolded proteins accumulate in the ER (Kondo et al, 2005;Okada et al, 2003;Shen et al, 2002;Zhang et al, 2006). By these means, diverse cellular function can be regulated by a single Rip mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

Nadanaka

Yoshida

Sato

et al. 2006

Cell Struct. Funct.

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ABSTRACT. Mammalian transcription factor ATF6 is constitutively synthesized as a type II transmembrane protein embedded in the endoplasmic reticulum (ER). It is activated when unfolded proteins are accumulated in the ER under ER stress through a process called regulated intramembrane proteolysis (Rip), in which ATF6 is transported from the ER to the Golgi apparatus where it undergoes sequential cleavage by Site-1 and Site-2 proteases. The cytosolic transcription factor domain of ATF6 liberated from the Golgi membrane enters the nucleus where it activates transcription of ER-localized molecular chaperones and folding enzymes, leading to the maintenance of the homeostasis of the ER. Here, we analyzed M19 cells, a mutant of Chinese hamster ovary cells deficient in Site-2 protease. It was previously shown that M19 cells are defective in the induction of mRNA encoding the major ER chaperone BiP. In M19 cells, ATF6 was not converted from the membrane-bound precursor form to the cleaved and nuclear form as expected. Moreover, some of the ATF6 was constitutively relocated to the Golgi apparatus, where it was cleaved by Site-1 protease, and remained associated with the Golgi apparatus, indicating that the ER of M19 cells was constitutively stressed. Consistent with this notion, the two other ER stress response mediators, IRE1 and PERK, were also constitutively activated in M19 cells. M19 cells showed inefficient secretion of a model protein. These results suggest that Rip-mediated activation of ATF6 is important for the homeostasis of the ER in not only ER-stressed but also unstressed cells.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

Nadanaka

Yoshida

Sato

et al. 2006

Cell Struct. Funct.

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“…CREBH is cleaved on ER stress and activates the expression of acute response genes [23]. A recent study showed that CREBH is nutritionally regulated [24].…”

Section: Introductionmentioning

confidence: 99%

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min

Jeong

et al. 2012

Diabetologia

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Aims/hypothesis Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis. Methods The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production. Results Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, AdCrebh inhibited insulin-and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo. Conclusions/interpretation These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.

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“…Predictably, AIbZIP, one of OASIS family proteins, has a role in differentiation of sperms by two papers regarding its knockout mice (44,45). CREBH, another OASIS family member, has a role to activate expression of inflammatory response in the liver (13). Besides OASIS family proteins, canonical ER stress transducers have also been defined to play roles in development, differentiation, and maturation of the cells.…”

Section: Resultsmentioning

confidence: 99%

Physiological unfolded protein response regulated by OASIS family members, transmembrane bZIP transcription factors

et al. 2011

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SummaryThe endoplasmic reticulum (ER) plays role in the maintenance of numerous aspects of cellular and organismal homeostasis by folding, modifying, and exporting nascent secretory and transmembrane proteins. Failure of the ER's adaptive capacity results in accumulation of unfolded or malfolded proteins in the ER lumen (ER stress). To avoid cellular damage, mammalian cells activate the specific signals from the ER to the cytosol or nucleus to enhance the capacity for protein folding, attenuate the synthesis of proteins, and degrade unfolded proteins. These signaling pathways are collectively known as the unfolded protein response (UPR). The canonical branches of the UPR are mediated by three ER membrane-bound proteins, PERK, IRE1, and ATF6. These ER stress transducers basically play important roles in cell survival after ER stress. Recently, novel types of ER stress transducers, OASIS family members that share a region of high sequence similarity with ATF6 have been identified. They have a transmembrane domain, which allows them to associate with the ER, and possess a transcription-activation domain and a bZIP domain. OASIS family proteins include OASIS, BBF2H7, CREBH, AIbZIP, and Luman. Despite the structural similarities among OASIS family proteins and ATF6, differences in activating stimuli, tissue distribution, and response element binding indicate specialized functions of each member on regulating the UPR in the specific organs and tissues. Here, we summarize our current understanding of biochemical characteristics and in vivo functions of OASIS family proteins, particularly focusing on OASIS and BBF2H7. A growing body of new works suggests that the UPR branches regulated by OASIS family members play essential roles in cell differentiation and maturation or maintenance of basal cellular homeostasis in mammals.

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Endoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response

Cited by 715 publications

References 44 publications

Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Physiological unfolded protein response regulated by OASIS family members, transmembrane bZIP transcription factors

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