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Endoplasmic reticulum stress in periimplantation embryos.

Michalak M, Gye MC - Clin Exp Reprod Med (2015)

Bottom Line: As such, the UPR-associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos.Attenuation of ER stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos.Further elucidation of new and relevant ER stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.

ABSTRACT
Stress coping mechanisms are critical to minimize or overcome damage caused by ever changing environmental conditions. They are designed to promote cell survival. The unfolded protein response (UPR) pathway is mobilized in response to the accumulation of unfolded proteins, ultimately in order to regain endoplasmic reticulum (ER) homeostasis. Various elements of coping responses to ER stress including Perk, Ask1, Bip, Chop, Gadd34, Ire1, Atf4, Atf6, and Xbp1 have been identified and were found to be inducible in oocytes and preimplantation embryos, suggesting that, as a normal part of the cellular adaptive mechanism, these coping responses, including the UPR, play a pivotal role in the development of preimplantation embryos. As such, the UPR-associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos. After implantation, ER stress-induced coping responses become physiologically important for a normal decidual response, placentation, and early organogenesis. Attenuation of ER stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos. Further elucidation of new and relevant ER stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro.

No MeSH data available.


Related in: MedlinePlus

Unfolded protein response (UPR) pathways. Three endoplasmic reticulum (ER) transmembrane proteins--the ER kinase dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone BiP, comprise the UPR reaction to ER stress. Under unstressed conditions, BiP directly interacts with IRE, PERK, and ATF6, but upon an increase in misfolded protein, BiP is sequestered away from these inducers, allowing activation of the UPR. PERK triggers its dimerization and autophosphorylation, followed by phosphorylation of eIF2α, preventing initiation of translation. ATF6 is an ER transmembrane protein cleaved in the Golgi. Cleavage of ATF6 produces a soluble basic leucine zipper (bZIP) transcription factor (cleaved ATF6) that binds to ER stress response elements (ERSE-I and II) to induce transcriptional activation of ER stress response genes. The transmembrane IRE1 dimerizes, leading to activation of kinase and endoribonuclease activity and splicing of the X-box binding protein 1 (XBP1) mRNA to produce an altered reading frame XBP1s mRNA. The XBP1s splice variant binds to the specific promoter elements, ERSE and unfolded protein response (UPRE), triggering transactivation of downstream UPR responsive genes, which are part of protein folding quality control and degradation machinery. ERAD, ER-associated degradation; sXBP1, splices XBP1.
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Figure 1: Unfolded protein response (UPR) pathways. Three endoplasmic reticulum (ER) transmembrane proteins--the ER kinase dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone BiP, comprise the UPR reaction to ER stress. Under unstressed conditions, BiP directly interacts with IRE, PERK, and ATF6, but upon an increase in misfolded protein, BiP is sequestered away from these inducers, allowing activation of the UPR. PERK triggers its dimerization and autophosphorylation, followed by phosphorylation of eIF2α, preventing initiation of translation. ATF6 is an ER transmembrane protein cleaved in the Golgi. Cleavage of ATF6 produces a soluble basic leucine zipper (bZIP) transcription factor (cleaved ATF6) that binds to ER stress response elements (ERSE-I and II) to induce transcriptional activation of ER stress response genes. The transmembrane IRE1 dimerizes, leading to activation of kinase and endoribonuclease activity and splicing of the X-box binding protein 1 (XBP1) mRNA to produce an altered reading frame XBP1s mRNA. The XBP1s splice variant binds to the specific promoter elements, ERSE and unfolded protein response (UPRE), triggering transactivation of downstream UPR responsive genes, which are part of protein folding quality control and degradation machinery. ERAD, ER-associated degradation; sXBP1, splices XBP1.

Mentions: ER stress is caused by a disruption in cellular energy and/or nutrient homeostasis. It impairs ER functions such as protein folding and the heat shock response, and leads to altered Ca2+ levels and nutrient starvation. Activation of ER stress can result in the buildup of misfolded proteins in the ER and activation of the UPR as a coping strategy (Figure 1) [1]. The UPR involves distinct components designed to reestablish the protein synthesis machinery (Figure 1). These include (1) translational attenuation to arrest the entry of new proteins into the ER; (2) transcriptional activation of genes encoding proteins involved in protein folding to assist the maturation of proteins; (3) transcriptional activation of genes for components of the ER-associated protein degradation (ERAD) system to decrease the number of misfolded proteins; and if these are not successful, (4) activation of apoptotic pathways to eliminate defective cells [4,9,10]. Three ER transmembrane proteins: dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone immunoglobulin binding protein (BiP, also known as glucose-regulated protein [GRP] 78), compose the UPR, an ER stress coping response. GRP78/BiP is a centrally located modulator/sensor of the UPR coping response. It is a monomeric, globular protein that functionally sorts and releases terminally misfolded substrates to the ERAD pathway. Under non-stressed conditions GRP78/BiP interacts with IRE, PERK, and ATF6, but upon an increase in misfolded proteins, GRP78/BiP is sequestered away from these inducers, leading to the activation of the UPR.


Endoplasmic reticulum stress in periimplantation embryos.

Michalak M, Gye MC - Clin Exp Reprod Med (2015)

Unfolded protein response (UPR) pathways. Three endoplasmic reticulum (ER) transmembrane proteins--the ER kinase dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone BiP, comprise the UPR reaction to ER stress. Under unstressed conditions, BiP directly interacts with IRE, PERK, and ATF6, but upon an increase in misfolded protein, BiP is sequestered away from these inducers, allowing activation of the UPR. PERK triggers its dimerization and autophosphorylation, followed by phosphorylation of eIF2α, preventing initiation of translation. ATF6 is an ER transmembrane protein cleaved in the Golgi. Cleavage of ATF6 produces a soluble basic leucine zipper (bZIP) transcription factor (cleaved ATF6) that binds to ER stress response elements (ERSE-I and II) to induce transcriptional activation of ER stress response genes. The transmembrane IRE1 dimerizes, leading to activation of kinase and endoribonuclease activity and splicing of the X-box binding protein 1 (XBP1) mRNA to produce an altered reading frame XBP1s mRNA. The XBP1s splice variant binds to the specific promoter elements, ERSE and unfolded protein response (UPRE), triggering transactivation of downstream UPR responsive genes, which are part of protein folding quality control and degradation machinery. ERAD, ER-associated degradation; sXBP1, splices XBP1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390675&req=5

Figure 1: Unfolded protein response (UPR) pathways. Three endoplasmic reticulum (ER) transmembrane proteins--the ER kinase dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone BiP, comprise the UPR reaction to ER stress. Under unstressed conditions, BiP directly interacts with IRE, PERK, and ATF6, but upon an increase in misfolded protein, BiP is sequestered away from these inducers, allowing activation of the UPR. PERK triggers its dimerization and autophosphorylation, followed by phosphorylation of eIF2α, preventing initiation of translation. ATF6 is an ER transmembrane protein cleaved in the Golgi. Cleavage of ATF6 produces a soluble basic leucine zipper (bZIP) transcription factor (cleaved ATF6) that binds to ER stress response elements (ERSE-I and II) to induce transcriptional activation of ER stress response genes. The transmembrane IRE1 dimerizes, leading to activation of kinase and endoribonuclease activity and splicing of the X-box binding protein 1 (XBP1) mRNA to produce an altered reading frame XBP1s mRNA. The XBP1s splice variant binds to the specific promoter elements, ERSE and unfolded protein response (UPRE), triggering transactivation of downstream UPR responsive genes, which are part of protein folding quality control and degradation machinery. ERAD, ER-associated degradation; sXBP1, splices XBP1.
Mentions: ER stress is caused by a disruption in cellular energy and/or nutrient homeostasis. It impairs ER functions such as protein folding and the heat shock response, and leads to altered Ca2+ levels and nutrient starvation. Activation of ER stress can result in the buildup of misfolded proteins in the ER and activation of the UPR as a coping strategy (Figure 1) [1]. The UPR involves distinct components designed to reestablish the protein synthesis machinery (Figure 1). These include (1) translational attenuation to arrest the entry of new proteins into the ER; (2) transcriptional activation of genes encoding proteins involved in protein folding to assist the maturation of proteins; (3) transcriptional activation of genes for components of the ER-associated protein degradation (ERAD) system to decrease the number of misfolded proteins; and if these are not successful, (4) activation of apoptotic pathways to eliminate defective cells [4,9,10]. Three ER transmembrane proteins: dsRNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1), in combination with the ER molecular chaperone immunoglobulin binding protein (BiP, also known as glucose-regulated protein [GRP] 78), compose the UPR, an ER stress coping response. GRP78/BiP is a centrally located modulator/sensor of the UPR coping response. It is a monomeric, globular protein that functionally sorts and releases terminally misfolded substrates to the ERAD pathway. Under non-stressed conditions GRP78/BiP interacts with IRE, PERK, and ATF6, but upon an increase in misfolded proteins, GRP78/BiP is sequestered away from these inducers, leading to the activation of the UPR.

Bottom Line: As such, the UPR-associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos.Attenuation of ER stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos.Further elucidation of new and relevant ER stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.

ABSTRACT
Stress coping mechanisms are critical to minimize or overcome damage caused by ever changing environmental conditions. They are designed to promote cell survival. The unfolded protein response (UPR) pathway is mobilized in response to the accumulation of unfolded proteins, ultimately in order to regain endoplasmic reticulum (ER) homeostasis. Various elements of coping responses to ER stress including Perk, Ask1, Bip, Chop, Gadd34, Ire1, Atf4, Atf6, and Xbp1 have been identified and were found to be inducible in oocytes and preimplantation embryos, suggesting that, as a normal part of the cellular adaptive mechanism, these coping responses, including the UPR, play a pivotal role in the development of preimplantation embryos. As such, the UPR-associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos. After implantation, ER stress-induced coping responses become physiologically important for a normal decidual response, placentation, and early organogenesis. Attenuation of ER stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos. Further elucidation of new and relevant ER stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro.

No MeSH data available.


Related in: MedlinePlus