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Signaling pathways from the endoplasmic reticulum and their roles in disease.

Kadowaki H, Nishitoh H - Genes (Basel) (2013)

Bottom Line: However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations.Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases.In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. kadowaki@med.miyazaki-u.ac.jp.

ABSTRACT
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

No MeSH data available.


Related in: MedlinePlus

Apoptosis signaling under ER stress conditions. Prolonged or severe ER stress, as well as dysfunction of the unfolded protein response (UPR), induces apoptosis signaling, primarily through the IRE1 and PERK pathways. In the IRE1 pathway, activated IRE1 recruits TRAF2 and ASK1 on the ER membrane and activates the ASK1-dependent apoptosis pathway. In addition, the IKK-NFκB pathway is also activated by IRE1-TRAF2 and induces an apoptotic response. Proapoptotic Bcl-2 family members, Bax and Bak, interact with IRE1 and promote its RNase/kinase activity. Moreover, IRE1 induces ER-localized mRNA degradation. In the PERK pathway, ATF4 induced by the PERK-eIF2α pathway upregulates the expression of CHOP, which in turn activates the transcription of GADD34, ER oxidoreductase 1 (ERO1), and many proapoptotic factors. GADD34 then promotes dephosphorylation of eIF2α with PP1, canceling translational attenuation, and leads to an increase of protein loads into the ER. Furthermore, the translational attenuation of global proteins by the PERK-eIF2α pathway also applies to IκB, which has been terminally linked to the activation of NFκB.
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genes-04-00306-f002: Apoptosis signaling under ER stress conditions. Prolonged or severe ER stress, as well as dysfunction of the unfolded protein response (UPR), induces apoptosis signaling, primarily through the IRE1 and PERK pathways. In the IRE1 pathway, activated IRE1 recruits TRAF2 and ASK1 on the ER membrane and activates the ASK1-dependent apoptosis pathway. In addition, the IKK-NFκB pathway is also activated by IRE1-TRAF2 and induces an apoptotic response. Proapoptotic Bcl-2 family members, Bax and Bak, interact with IRE1 and promote its RNase/kinase activity. Moreover, IRE1 induces ER-localized mRNA degradation. In the PERK pathway, ATF4 induced by the PERK-eIF2α pathway upregulates the expression of CHOP, which in turn activates the transcription of GADD34, ER oxidoreductase 1 (ERO1), and many proapoptotic factors. GADD34 then promotes dephosphorylation of eIF2α with PP1, canceling translational attenuation, and leads to an increase of protein loads into the ER. Furthermore, the translational attenuation of global proteins by the PERK-eIF2α pathway also applies to IκB, which has been terminally linked to the activation of NFκB.

Mentions: In mammals, the UPR signaling pathway is initiated by three ER membrane-associated sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK) (Figure 1). If the survival signal is insufficient to relieve the cells from ER stress, cells may undergo apoptosis to destroy ER stress-damaged cells. Many reports have shown that several molecules, including IRE1 [5,6], apoptosis signal-regulating kinase 1 (ASK1) [7], Bax/Bak [8,9,10], PERK, eIF2α-activating transcription factor-4 (ATF4) [11], and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP, also known as a growth arrest- and DNA damage-inducible gene 153 (GADD153)) [12,13], are related to ER stress-induced apoptosis signaling pathways (Figure 2). Dysfunction of the UPR, or prolonged ER stress, disrupts ER homeostasis. A large number of groups have described the relation between ER stress responses and a variety of human diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Therefore, it is important to understand the role of the UPR in the pathogenesis of these diseases. In this review, we summarize the molecular mechanisms of ER stress-induced survival and apoptosis signaling pathways and discuss the possibility that UPR signaling components could serve as potent therapeutic targets for the treatment of diseases.


Signaling pathways from the endoplasmic reticulum and their roles in disease.

Kadowaki H, Nishitoh H - Genes (Basel) (2013)

Apoptosis signaling under ER stress conditions. Prolonged or severe ER stress, as well as dysfunction of the unfolded protein response (UPR), induces apoptosis signaling, primarily through the IRE1 and PERK pathways. In the IRE1 pathway, activated IRE1 recruits TRAF2 and ASK1 on the ER membrane and activates the ASK1-dependent apoptosis pathway. In addition, the IKK-NFκB pathway is also activated by IRE1-TRAF2 and induces an apoptotic response. Proapoptotic Bcl-2 family members, Bax and Bak, interact with IRE1 and promote its RNase/kinase activity. Moreover, IRE1 induces ER-localized mRNA degradation. In the PERK pathway, ATF4 induced by the PERK-eIF2α pathway upregulates the expression of CHOP, which in turn activates the transcription of GADD34, ER oxidoreductase 1 (ERO1), and many proapoptotic factors. GADD34 then promotes dephosphorylation of eIF2α with PP1, canceling translational attenuation, and leads to an increase of protein loads into the ER. Furthermore, the translational attenuation of global proteins by the PERK-eIF2α pathway also applies to IκB, which has been terminally linked to the activation of NFκB.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924831&req=5

genes-04-00306-f002: Apoptosis signaling under ER stress conditions. Prolonged or severe ER stress, as well as dysfunction of the unfolded protein response (UPR), induces apoptosis signaling, primarily through the IRE1 and PERK pathways. In the IRE1 pathway, activated IRE1 recruits TRAF2 and ASK1 on the ER membrane and activates the ASK1-dependent apoptosis pathway. In addition, the IKK-NFκB pathway is also activated by IRE1-TRAF2 and induces an apoptotic response. Proapoptotic Bcl-2 family members, Bax and Bak, interact with IRE1 and promote its RNase/kinase activity. Moreover, IRE1 induces ER-localized mRNA degradation. In the PERK pathway, ATF4 induced by the PERK-eIF2α pathway upregulates the expression of CHOP, which in turn activates the transcription of GADD34, ER oxidoreductase 1 (ERO1), and many proapoptotic factors. GADD34 then promotes dephosphorylation of eIF2α with PP1, canceling translational attenuation, and leads to an increase of protein loads into the ER. Furthermore, the translational attenuation of global proteins by the PERK-eIF2α pathway also applies to IκB, which has been terminally linked to the activation of NFκB.
Mentions: In mammals, the UPR signaling pathway is initiated by three ER membrane-associated sensors: activating transcription factor-6 (ATF6), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and double-stranded RNA-dependent protein kinase (PKR)-like eukaryotic initiation factor 2α (eIF2α) kinase (PERK) (Figure 1). If the survival signal is insufficient to relieve the cells from ER stress, cells may undergo apoptosis to destroy ER stress-damaged cells. Many reports have shown that several molecules, including IRE1 [5,6], apoptosis signal-regulating kinase 1 (ASK1) [7], Bax/Bak [8,9,10], PERK, eIF2α-activating transcription factor-4 (ATF4) [11], and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP, also known as a growth arrest- and DNA damage-inducible gene 153 (GADD153)) [12,13], are related to ER stress-induced apoptosis signaling pathways (Figure 2). Dysfunction of the UPR, or prolonged ER stress, disrupts ER homeostasis. A large number of groups have described the relation between ER stress responses and a variety of human diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Therefore, it is important to understand the role of the UPR in the pathogenesis of these diseases. In this review, we summarize the molecular mechanisms of ER stress-induced survival and apoptosis signaling pathways and discuss the possibility that UPR signaling components could serve as potent therapeutic targets for the treatment of diseases.

Bottom Line: However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations.Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases.In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. kadowaki@med.miyazaki-u.ac.jp.

ABSTRACT
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis, as well as the possible roles of ER stress in several diseases.

No MeSH data available.


Related in: MedlinePlus