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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

Mammalian ERAD: the HRD1 complex. ER luminal misfolded proteins are recognized by machinery including ER chaperone BiP, DnaJ family ERdj5, and lectins, such as ER degradation enhancing alpha-mannosidase-like protein (EDEM) family members, OS-9, and XTP3-B. Following its recognition, the terminally misfolded protein is recruited to the HRD1 complex via binding with SEL1L and is then brought to a putative retrotranslocon channel, which may include Derlin family proteins, HRD1, or the Sec61 complex. Finally, the protein is dislocated from the ER to the cytosol. Cytoplasm-exposed substrates are ubiquitinated by E3 ubiquitin ligase HRD1, and extracted by the p97-Npl4-Ufd1 complex anchored on the ER transmembrane through VIMP in an ATP-dependent manner. Finally, the extracted substrate is deglycosylated by PNGase, deubiquitinated, and degraded by the proteasome.
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genes-04-00306-f003: Mammalian ERAD: the HRD1 complex. ER luminal misfolded proteins are recognized by machinery including ER chaperone BiP, DnaJ family ERdj5, and lectins, such as ER degradation enhancing alpha-mannosidase-like protein (EDEM) family members, OS-9, and XTP3-B. Following its recognition, the terminally misfolded protein is recruited to the HRD1 complex via binding with SEL1L and is then brought to a putative retrotranslocon channel, which may include Derlin family proteins, HRD1, or the Sec61 complex. Finally, the protein is dislocated from the ER to the cytosol. Cytoplasm-exposed substrates are ubiquitinated by E3 ubiquitin ligase HRD1, and extracted by the p97-Npl4-Ufd1 complex anchored on the ER transmembrane through VIMP in an ATP-dependent manner. Finally, the extracted substrate is deglycosylated by PNGase, deubiquitinated, and degraded by the proteasome.

Mentions: Although it has been reported that a variety of E3 ligases, including HRD1, gp78, RMA1/RNF5, TRC8, and TEB4 (Doa10p in yeast), can function in the mammalian ERAD pathway [69], the molecular mechanisms of the ERAD-C, ERAD-L, and ERAD-M pathways remain unclear. HRD1 is also known as synoviolin and functions as the E3 ligase for ubiquitination of substrates such as TCR-α, CD3-δ, and Parkin-associated endothelin-like receptors (Pael-R) [70,71,72]. In regard to the function of the HRD1 complex in the ERAD pathway (Figure 3), some misfolded glycoproteins are first recognized by ER degradation enhancing alpha-mannosidase-like protein (EDEM) family proteins (Htm1p/Mnl1p in yeast), which include EDEM1, EDEM2, and EDEM3 [73]. EDEM family proteins are α-mannosidase-like lectins that are induced by the UPR and bind to the misfolded glycoproteins with a mannose 8 structure [74,75,76]. Although EDEM3, but not EDEM1 or EDEM2, exhibits mannosidase activity, all of the EDEM family proteins play crucial roles in ERAD [73,77]. A recent study has shown that the ER-resident protein ERdj5 exhibits reductase activity, cleaves the disulfide bonds of misfolded proteins, and accelerates ERAD activity through its association with EDEM1 and BiP [78]. Moreover, in addition to misfolded glycoproteins, non-glycoproteins are also recognized by luminal lectins, such as osteosarcoma amplified 9 (OS-9) and XTP3-transactivated gene B protein (XTP3-B), which are mammalian homologs of Yos9p.


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

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

Mammalian ERAD: the HRD1 complex. ER luminal misfolded proteins are recognized by machinery including ER chaperone BiP, DnaJ family ERdj5, and lectins, such as ER degradation enhancing alpha-mannosidase-like protein (EDEM) family members, OS-9, and XTP3-B. Following its recognition, the terminally misfolded protein is recruited to the HRD1 complex via binding with SEL1L and is then brought to a putative retrotranslocon channel, which may include Derlin family proteins, HRD1, or the Sec61 complex. Finally, the protein is dislocated from the ER to the cytosol. Cytoplasm-exposed substrates are ubiquitinated by E3 ubiquitin ligase HRD1, and extracted by the p97-Npl4-Ufd1 complex anchored on the ER transmembrane through VIMP in an ATP-dependent manner. Finally, the extracted substrate is deglycosylated by PNGase, deubiquitinated, and degraded by the proteasome.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

genes-04-00306-f003: Mammalian ERAD: the HRD1 complex. ER luminal misfolded proteins are recognized by machinery including ER chaperone BiP, DnaJ family ERdj5, and lectins, such as ER degradation enhancing alpha-mannosidase-like protein (EDEM) family members, OS-9, and XTP3-B. Following its recognition, the terminally misfolded protein is recruited to the HRD1 complex via binding with SEL1L and is then brought to a putative retrotranslocon channel, which may include Derlin family proteins, HRD1, or the Sec61 complex. Finally, the protein is dislocated from the ER to the cytosol. Cytoplasm-exposed substrates are ubiquitinated by E3 ubiquitin ligase HRD1, and extracted by the p97-Npl4-Ufd1 complex anchored on the ER transmembrane through VIMP in an ATP-dependent manner. Finally, the extracted substrate is deglycosylated by PNGase, deubiquitinated, and degraded by the proteasome.
Mentions: Although it has been reported that a variety of E3 ligases, including HRD1, gp78, RMA1/RNF5, TRC8, and TEB4 (Doa10p in yeast), can function in the mammalian ERAD pathway [69], the molecular mechanisms of the ERAD-C, ERAD-L, and ERAD-M pathways remain unclear. HRD1 is also known as synoviolin and functions as the E3 ligase for ubiquitination of substrates such as TCR-α, CD3-δ, and Parkin-associated endothelin-like receptors (Pael-R) [70,71,72]. In regard to the function of the HRD1 complex in the ERAD pathway (Figure 3), some misfolded glycoproteins are first recognized by ER degradation enhancing alpha-mannosidase-like protein (EDEM) family proteins (Htm1p/Mnl1p in yeast), which include EDEM1, EDEM2, and EDEM3 [73]. EDEM family proteins are α-mannosidase-like lectins that are induced by the UPR and bind to the misfolded glycoproteins with a mannose 8 structure [74,75,76]. Although EDEM3, but not EDEM1 or EDEM2, exhibits mannosidase activity, all of the EDEM family proteins play crucial roles in ERAD [73,77]. A recent study has shown that the ER-resident protein ERdj5 exhibits reductase activity, cleaves the disulfide bonds of misfolded proteins, and accelerates ERAD activity through its association with EDEM1 and BiP [78]. Moreover, in addition to misfolded glycoproteins, non-glycoproteins are also recognized by luminal lectins, such as osteosarcoma amplified 9 (OS-9) and XTP3-transactivated gene B protein (XTP3-B), which are mammalian homologs of Yos9p.

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