The Endoplasmic Reticulum Stress Transducer BBF2H7 Suppresses Apoptosis by Activating the ATF5-MCL1 Pathway in Growth Plate Cartilage

Izumi, Soutarou; Saito, Atsushi; Kanemoto, Soshi; Kawasaki, Noritaka; Asada, Rie; Iwamoto, Hideo; Oki, Mami; Miyagi, Hidetaka; Ochi, Mitsuo; Imaizumi, Kazunori

doi:10.1074/jbc.m112.373746

Cited by 34 publications

(32 citation statements)

References 46 publications

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“…Chondrocytes express the ATF6 homolog, BBF2H7, which may prevent CHOP-mediated apoptotic signaling [72]. In models of MCDS, UPR activation in hypertrophic chondrocytes results in the dedifferentiation of chondrocytes to a prehypertrophic state [48,107].…”

Section: Discussionmentioning

confidence: 99%

“…In BBF2H7 −/− mice, chondrocyte proliferation is severely perturbed (Table 2), and this is likely to be due to the insufficient secretion of ECM proteins required for chondrocyte maturation in the growth plate [60]. Interestingly, BBF2H7 also appears to have a key role in preventing UPR-induced apoptosis in chondrocytes [72]. This could explain earlier findings in metaphyseal chondrodysplasia, Schmid type (MCDS) chondrocytes, which do not undergo apoptosis despite elevated CHOP expression [48,73].…”

Section: The Unfolded Protein Response Has An Essential Role In Chmentioning

confidence: 99%

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Hughes

Oxford

Tawara

et al. 2017

IJMS

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Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.

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Section: Discussionmentioning

confidence: 99%

Section: The Unfolded Protein Response Has An Essential Role In Chmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Hughes

Oxford

Tawara

et al. 2017

IJMS

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“…Newman and Keating also reported that ATF5 acted as a C/EBPcbinding transcription factor in comprehensive protein array analysis [30]. ATF5 is a stress response transcription factor whose expression is regulated by posttranscriptional regulation [31], translational regulation [32,33] and post-translational regulation [34][35][36][37][38][39][40] in response to cellular stresses including endoplasmic reticulum (ER) stress [33,41], arsenite exposure [32,33,36] and amino acid limitation [31,32]. Limitation of a single amino acid (glutamine, methionine or leucine) in the cell culture medium increased ATF5 mRNA levels in HeLaS3 cells [31].…”

Section: Introductionmentioning

confidence: 99%

The 5′‐untranslated region regulates ATF5 mRNA stability via nonsense‐mediated mRNA decay in response to environmental stress

et al. 2013

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We previously reported that activating transcription factor 5 (ATF5) mRNA increases in response to amino acid limitation, and that this increase is dependent on mRNA stabilization. The ATF5 gene allows transcription of mRNAs with two alternative 5′-UTRs, 5′-UTRa and 5′-UTRb, derived from exon 1a and exon 1b. 5′-UTRa contains the upstream open reading frames uORF1 and uORF2. Phosphorylation of eukaryotic initiation factor 2a during the integrated stress response had been previously shown to lead to bypassing of uORF2 translation and production of ATF5 protein. Translation of uORF2 is expected to result in translational termination at a position 125 nucleotides upstream of the exon junction, and this fits the criterion of a nonsense-mediated decay target mRNA. We investigated the potential role of 5′-UTRa in the control of mRNA stabilization, and found that 5′-UTRa reduced the stability of ATF5 mRNA. 5′-UTRa-regulated destabilization of mRNA was suppressed by knockdown of the nonsense-mediated decay factors Upf1 and Upf2. Mutation of the downstream AUG (uAUG2) rendered mRNA refractory to Upf1 and Upf2 knockdown. Moreover, 5′-UTRa-regulated down-regulation was hindered by amino acid limitation and tunicamycin treatment, and stressinduced phosphorylation of eukaryotic initiation factor 2a was involved in stabilization of ATF5 mRNA. These studies show that ATF5 mRNA is a naturally occurring normal mRNA target of nonsense-mediated decay, and provide evidence for linkage between stress-regulated translational regulation and the mRNA decay pathway. This linkage constitutes a mechanism that regulates expression of stress response genes.

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“…Related to this finding, but somewhat perplexing is the observation that chemical inhibition of LonP1 protease activity using CDDO activates the UPR mt , as well as increasing ATF4 mediated gene induction (75), indicating a possible bidirectional regulatory linkage between ATF4 and LonP1. Another finding that could serve as a molecular integration point between the UPR ER and UPR mt was shown in chondrocytes, where the ATF6 family member, BBF2H7, induces typical UPR ER genes, as well as the regulator of the UPR mt , ATF5 (76). In an examination of the effects of drugs that dysregulate mitochondrial proteostasis in HeLa, 293T, and COS7 cells, as well as maneuvers that cause mitochondrial proteostatic stress, in vivo, it was shown that via activation of the ISR, ATF4 but not ATF5 responds to dysregulated mitochondrial proteostasis and activates the expression of cytoprotective genes (77).…”

Section: Integrating Er and Mitochondrial Proteostasismentioning

confidence: 98%

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

Arrieta

Blackwood

Stauffer

et al. 2020

Front. Cardiovasc. Med.

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The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.

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The Endoplasmic Reticulum Stress Transducer BBF2H7 Suppresses Apoptosis by Activating the ATF5-MCL1 Pathway in Growth Plate Cartilage

Abstract: Background:The endoplasmic reticulum stress transducer BBF2H7 is expressed in proliferating chondrocytes. Results: Apoptosis is promoted in the cartilage of Bbf2h7 Ϫ/Ϫ mice. BBF2H7 activates Atf5 transcription, followed by apoptosis

Cited by 34 publications

References 46 publications

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

The 5′‐untranslated region regulates ATF5 mRNA stability via nonsense‐mediated mRNA decay in response to environmental stress

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

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