Glycosylation-independent ERAD pathway serves as a backup system under ER stress

Ushioda, Ryo; Hoseki, Jun; Nagata, Kazuhiro

doi:10.1091/mbc.e13-03-0138

Cited by 78 publications

(73 citation statements)

References 30 publications

(19 reference statements)

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“…1B and C). Structural prediction analysis using i-TASSER (21,22,28) showed that ElpA is similar to the endoplasmic reticulum (ER) protein ERdj5 (data not shown), a TMH-containing, ER-resident disulfide reductase that functions in retrotranslocation of proteins destined for ubiquitin-mediated degradation (29). ElpA contains a predicted thioredoxin fold similar to ERdj5 in the N-terminal region of the effector.…”

Section: Resultsmentioning

confidence: 99%

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

et al. 2015

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Coxiella burnetii causes human Q fever, a zoonotic disease that presents with acute flu-like symptoms and can result in chronic life-threatening endocarditis. In human alveolar macrophages, C. burnetii uses a Dot/Icm type IV secretion system (T4SS) to generate a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. The T4SS translocates effector proteins, or substrates, into the host cytosol, where they mediate critical cellular events, including interaction with autophagosomes, PV formation, and prevention of apoptosis. Over 100 C. burnetii Dot/Icm substrates have been identified, but the function of most remains undefined. Here, we identified a novel Dot/Icm substrate-encoding open reading frame (CbuD1884) present in all C. burnetii isolates except the Nine Mile reference isolate, where the gene is disrupted by a frameshift mutation, resulting in a pseudogene. The CbuD1884 protein contains two transmembrane helices (TMHs) and a coiled-coil domain predicted to mediate protein-protein interactions. The C-terminal region of the protein contains a predicted Dot/Icm translocation signal and was secreted by the T4SS, while the N-terminal portion of the protein was not secreted. When ectopically expressed in eukaryotic cells, the TMH-containing N-terminal region of the CbuD1884 protein trafficked to the endoplasmic reticulum (ER), with the C terminus dispersed nonspecifically in the host cytoplasm. This new Dot/Icm substrate is now termed ElpA (ER-localizing protein A). Full-length ElpA triggered substantial disruption of ER structure and host cell secretory transport. These results suggest that ElpA is a pathotype-specific T4SS effector that influences ER function during C. burnetii infection.

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Section: Resultsmentioning

confidence: 99%

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

et al. 2015

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“…This alternative NHEJ, termed alt-NHEJ or b-NHEJ (for backup NHEJ), operates with an order of magnitude slower kinetics, frequently joins incorrect ends, and is suppressed by the c-NHEJ (28,29). Additional examples of the existence of a backup pathway were also found in other cellular processes, such as cell death (30), endoplasmic reticulum-associated degradation (31), and mRNA decay (32). It is believed that evolution ensures the existence of a backup mechanism to prevent the failure of cellular processes that are critically important to life (33).…”

Section: Discussionmentioning

confidence: 99%

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Zhou¹,

Zhao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

160

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Cytokinesis in Trypanosoma brucei, an early branching protozoan, occurs along its longitudinal axis uni-directionally from the anterior tip of the new flagellum attachment zone filament toward the cell's posterior end. However, the underlying mechanisms remain elusive. Here we report that cytokinesis in T. brucei is regulated by a concerted action of Polo-like kinase, Aurora B kinase, and a trypanosome-specific protein CIF1. Phosphorylation of CIF1 by Polo-like kinase targets it to the anterior tip of the new flagellum attachment zone filament, where it subsequently recruits Aurora B kinase to initiate cytokinesis. Consistent with its role, CIF1 depletion inhibits cytokinesis initiation from the anterior end of the cell, but, surprisingly, triggers cytokinesis initiation from the posterior end of the cell, suggesting the activation of an alternative cytokinesis from the opposite cell end. Our results reveal the mechanistic roles of CIF1 and Polo-like kinase in cytokinesis initiation and elucidate the mechanism underlying the recruitment of Aurora B kinase to the cytokinesis initiation site at late anaphase. These findings also delineate a signaling cascade controlling cytokinesis initiation from the anterior end of the cell and uncover a backup cytokinesis that is initiated from the posterior end of the cell when the typical anterior-to-posterior cytokinesis is compromised.cytokinesis | Polo-like kinase | Aurora B kinase | backup cytokinesis |

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“…Glycoproteins misfolded in the ER are recognized by EDEM1 and are recruited to ERdj5, which reduces the intramolecular or intermolecular disulfide bonds of misfolded proteins to facilitate retro-translocation through the dislocon channel. When nonglycoproteins are misfolded in the ER or when EDEM1 is overwhelmed with misfolded glycoproteins, BiP recruits these misfolded proteins to ERdj5 (14). After reduction of disulfide bonds, substrates to be degraded are handed to BiP and recruited to the dislocon channel.…”

Section: Discussionmentioning

confidence: 99%

“…Misfolded substrates are transferred from ERdj5 to Binding Ig Protein (BiP), a major molecular chaperone in the ER, which binds to ERdj5 through the HPD (Hys-Pro-Asp) motif in the J domain. BiP recruits the substrates to the retrotranslocation channel to promote their ER-associated degradation (ERAD) pathway (13,14).…”

mentioning

confidence: 99%

Redox-assisted regulation of Ca ²⁺ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

Ushioda

Miyamoto

Inoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Calcium ion (Ca 2+ ) is an important second messenger that regulates numerous cellular functions. Intracellular Ca 2+ concentration ([Ca 2+ ]i) is strictly controlled by Ca 2+ channels and pumps on the endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endoplasmic reticulum calcium ATPase (SERCA), imports Ca 2+ from the cytosol into the ER in an ATPase activitydependent manner. The activity of SERCA2b, the ubiquitous isoform of SERCA, is negatively regulated by disulfide bond formation between two luminal cysteines. Here, we show that ERdj5, a mammalian ER disulfide reductase, which we reported to be involved in the ER-associated degradation of misfolded proteins, activates the pump function of SERCA2b by reducing its luminal disulfide bond.

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Glycosylation-independent ERAD pathway serves as a backup system under ER stress

Cited by 78 publications

References 30 publications

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Redox-assisted regulation of Ca ²⁺ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

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Glycosylation-independent ERAD pathway serves as a backup system under ER stress

Cited by 78 publications

References 30 publications

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

Identification of ElpA, a Coxiella burnetii Pathotype-Specific Dot/Icm Type IV Secretion System Substrate

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Redox-assisted regulation of Ca 2+ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

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Redox-assisted regulation of Ca ²⁺ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5