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Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage.

Ji C - Biomolecules (2015)

Bottom Line: Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body.The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function.Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest.

View Article: PubMed Central - PubMed

Affiliation: GI/Liver Division, Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA. chengji@usc.edu.

ABSTRACT
Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

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Related in: MedlinePlus

Potential Molecular Mechanisms of Alcohol-induced Unfolded Protein Responses in Endoplasmic Reticulum, Golgi Apparatus, Mitochondria, and Lysosomes. Alcohol and/or its metabolites induce accumulations of unfolded/misfolded proteins (depicted by ) in the four types of cellular organelles, which create a stress condition in each of the organelles. The stress activates specialized transcriptional programs (solid arrows) mediated by distinct transducer(s) in each organelle leading to either restoration of organellar protein homeostasis or contribution to cell death (dashed arrows). EtOH, alcohol and/or alcohol metabolites; UPRer or UPR, unfolded protein response in the endoplasmic reticulum (ER); BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein; IRE1α, inositol requiring enzyme 1α; ATF 4 or 6, activating transcription factor 4 or 6; nATF6, nuclear ATF6; PERK, PKR-like ER-localized eIF2α kinase; eIF2α, eukaryotic translation initiation factor 2α; uXBP1, un-spliced X-box binding protein 1; sXBP1, spliced XBP1; ERAD, ER associated degradation; CHOP, C/EBP homology protein 10. UPRgl, unfolded protein response in the Golgi apparatus; CREB3; a basic leucine zipper-containing transcription factor; TFE3, a basic-helix-loop-helix type transcription factor; ARF4, a member of the small GTPase family that regulates Golgi-to-ER vesicular transport; HSP47, a 47 kDa collagen-binding glycoprotein. UPRmt, unfolded protein response in the mitochondria; ROS, reactive oxygen species; ATFS-1, activating transcription factor associated with stress-1; AKT, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase; PKR, protein kinase RNA-activated also known as protein kinase R; Nrf1, the nuclear factor erythroid 2-related factor 1; SATBs, special AT-rich sequence-binding proteins; UBL5, ubiquitin-like 5; HSP10, 60 or 70, heat shock protein 10, 60 or 70 acting as mitochondrial chaperones. UPRly, unfolded protein response in the lysosomes; mTORC1, mammalian target of rapamycin complex 1; TFEB, transcription factor EB.
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biomolecules-05-01099-f001: Potential Molecular Mechanisms of Alcohol-induced Unfolded Protein Responses in Endoplasmic Reticulum, Golgi Apparatus, Mitochondria, and Lysosomes. Alcohol and/or its metabolites induce accumulations of unfolded/misfolded proteins (depicted by ) in the four types of cellular organelles, which create a stress condition in each of the organelles. The stress activates specialized transcriptional programs (solid arrows) mediated by distinct transducer(s) in each organelle leading to either restoration of organellar protein homeostasis or contribution to cell death (dashed arrows). EtOH, alcohol and/or alcohol metabolites; UPRer or UPR, unfolded protein response in the endoplasmic reticulum (ER); BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein; IRE1α, inositol requiring enzyme 1α; ATF 4 or 6, activating transcription factor 4 or 6; nATF6, nuclear ATF6; PERK, PKR-like ER-localized eIF2α kinase; eIF2α, eukaryotic translation initiation factor 2α; uXBP1, un-spliced X-box binding protein 1; sXBP1, spliced XBP1; ERAD, ER associated degradation; CHOP, C/EBP homology protein 10. UPRgl, unfolded protein response in the Golgi apparatus; CREB3; a basic leucine zipper-containing transcription factor; TFE3, a basic-helix-loop-helix type transcription factor; ARF4, a member of the small GTPase family that regulates Golgi-to-ER vesicular transport; HSP47, a 47 kDa collagen-binding glycoprotein. UPRmt, unfolded protein response in the mitochondria; ROS, reactive oxygen species; ATFS-1, activating transcription factor associated with stress-1; AKT, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase; PKR, protein kinase RNA-activated also known as protein kinase R; Nrf1, the nuclear factor erythroid 2-related factor 1; SATBs, special AT-rich sequence-binding proteins; UBL5, ubiquitin-like 5; HSP10, 60 or 70, heat shock protein 10, 60 or 70 acting as mitochondrial chaperones. UPRly, unfolded protein response in the lysosomes; mTORC1, mammalian target of rapamycin complex 1; TFEB, transcription factor EB.

Mentions: Alcohol induced ER stress response was initially reported in the liver of alcohol-fed mice, which involves ER chaperones (e.g., BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein), three ER resident sensors (i.e., IRE1 (inositol requiring enzyme 1), ATF6 (activating transcription factor 6), and PERK (double-stranded RNA-activated protein kinase (PKR)-like ER kinase), and transcription factors such as Xbp1 (X-box binding protein 1) and CHOP (C/EBP homology protein 10) (Figure 1) [25]. This initial discovery drew immediate attention as alcohol is mainly metabolized in the ER-rich hepatocytes. It is now known that alcohol-induced ER stress response occurs not only in liver but also in other major organs such as brain, pancreas and heart, and not only in rodents but also in other species, as well as in human alcoholics [23,24,25,26,27,28,29,30,31]. Several lines of molecular evidence substantially support an important role of alcohol-induced ER stress in damage of various organs, and disease development.


Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage.

Ji C - Biomolecules (2015)

Potential Molecular Mechanisms of Alcohol-induced Unfolded Protein Responses in Endoplasmic Reticulum, Golgi Apparatus, Mitochondria, and Lysosomes. Alcohol and/or its metabolites induce accumulations of unfolded/misfolded proteins (depicted by ) in the four types of cellular organelles, which create a stress condition in each of the organelles. The stress activates specialized transcriptional programs (solid arrows) mediated by distinct transducer(s) in each organelle leading to either restoration of organellar protein homeostasis or contribution to cell death (dashed arrows). EtOH, alcohol and/or alcohol metabolites; UPRer or UPR, unfolded protein response in the endoplasmic reticulum (ER); BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein; IRE1α, inositol requiring enzyme 1α; ATF 4 or 6, activating transcription factor 4 or 6; nATF6, nuclear ATF6; PERK, PKR-like ER-localized eIF2α kinase; eIF2α, eukaryotic translation initiation factor 2α; uXBP1, un-spliced X-box binding protein 1; sXBP1, spliced XBP1; ERAD, ER associated degradation; CHOP, C/EBP homology protein 10. UPRgl, unfolded protein response in the Golgi apparatus; CREB3; a basic leucine zipper-containing transcription factor; TFE3, a basic-helix-loop-helix type transcription factor; ARF4, a member of the small GTPase family that regulates Golgi-to-ER vesicular transport; HSP47, a 47 kDa collagen-binding glycoprotein. UPRmt, unfolded protein response in the mitochondria; ROS, reactive oxygen species; ATFS-1, activating transcription factor associated with stress-1; AKT, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase; PKR, protein kinase RNA-activated also known as protein kinase R; Nrf1, the nuclear factor erythroid 2-related factor 1; SATBs, special AT-rich sequence-binding proteins; UBL5, ubiquitin-like 5; HSP10, 60 or 70, heat shock protein 10, 60 or 70 acting as mitochondrial chaperones. UPRly, unfolded protein response in the lysosomes; mTORC1, mammalian target of rapamycin complex 1; TFEB, transcription factor EB.
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biomolecules-05-01099-f001: Potential Molecular Mechanisms of Alcohol-induced Unfolded Protein Responses in Endoplasmic Reticulum, Golgi Apparatus, Mitochondria, and Lysosomes. Alcohol and/or its metabolites induce accumulations of unfolded/misfolded proteins (depicted by ) in the four types of cellular organelles, which create a stress condition in each of the organelles. The stress activates specialized transcriptional programs (solid arrows) mediated by distinct transducer(s) in each organelle leading to either restoration of organellar protein homeostasis or contribution to cell death (dashed arrows). EtOH, alcohol and/or alcohol metabolites; UPRer or UPR, unfolded protein response in the endoplasmic reticulum (ER); BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein; IRE1α, inositol requiring enzyme 1α; ATF 4 or 6, activating transcription factor 4 or 6; nATF6, nuclear ATF6; PERK, PKR-like ER-localized eIF2α kinase; eIF2α, eukaryotic translation initiation factor 2α; uXBP1, un-spliced X-box binding protein 1; sXBP1, spliced XBP1; ERAD, ER associated degradation; CHOP, C/EBP homology protein 10. UPRgl, unfolded protein response in the Golgi apparatus; CREB3; a basic leucine zipper-containing transcription factor; TFE3, a basic-helix-loop-helix type transcription factor; ARF4, a member of the small GTPase family that regulates Golgi-to-ER vesicular transport; HSP47, a 47 kDa collagen-binding glycoprotein. UPRmt, unfolded protein response in the mitochondria; ROS, reactive oxygen species; ATFS-1, activating transcription factor associated with stress-1; AKT, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase; PKR, protein kinase RNA-activated also known as protein kinase R; Nrf1, the nuclear factor erythroid 2-related factor 1; SATBs, special AT-rich sequence-binding proteins; UBL5, ubiquitin-like 5; HSP10, 60 or 70, heat shock protein 10, 60 or 70 acting as mitochondrial chaperones. UPRly, unfolded protein response in the lysosomes; mTORC1, mammalian target of rapamycin complex 1; TFEB, transcription factor EB.
Mentions: Alcohol induced ER stress response was initially reported in the liver of alcohol-fed mice, which involves ER chaperones (e.g., BiP/GRP78, binding immunoglobulin protein also known as 78 kDa glucose-regulated protein), three ER resident sensors (i.e., IRE1 (inositol requiring enzyme 1), ATF6 (activating transcription factor 6), and PERK (double-stranded RNA-activated protein kinase (PKR)-like ER kinase), and transcription factors such as Xbp1 (X-box binding protein 1) and CHOP (C/EBP homology protein 10) (Figure 1) [25]. This initial discovery drew immediate attention as alcohol is mainly metabolized in the ER-rich hepatocytes. It is now known that alcohol-induced ER stress response occurs not only in liver but also in other major organs such as brain, pancreas and heart, and not only in rodents but also in other species, as well as in human alcoholics [23,24,25,26,27,28,29,30,31]. Several lines of molecular evidence substantially support an important role of alcohol-induced ER stress in damage of various organs, and disease development.

Bottom Line: Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body.The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function.Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest.

View Article: PubMed Central - PubMed

Affiliation: GI/Liver Division, Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA. chengji@usc.edu.

ABSTRACT
Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

Show MeSH
Related in: MedlinePlus