Pathogenic Hijacking of ER-Associated Degradation: Is ERAD Flexible?

Morito, Daisuke; Nagata, Kazuhiro

doi:10.1016/j.molcel.2015.06.010

Cited by 50 publications

(50 citation statements)

References 98 publications

(132 reference statements)

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“…As overall M2 levels are decreased in UBR4 KO cells (Figures 5D and 5E), we hypothesized that in absence of UBR4 IAV M2 is diverted from ER to autophagosomes for degradation. The cellular endoplasmic reticulum-associated degradation (ERAD) machinery is known to target membrane proteins from ER for degradation and is frequently exploited by different viruses (Morito and Nagata, 2015). Interestingly, DBeQ, an inhibitor of the ERAD regulatory protein p97 (Dugre et al, 1990), significantly rescued both M2 total and cell surface expression (Figure S5E).…”

Section: Resultsmentioning

confidence: 99%

Meta- and Orthogonal Integration of Influenza “OMICs” Data Defines a Role for UBR4 in Virus Budding

Tripathi

Pohl

Zhou

et al. 2015

Cell Host & Microbe

832

724

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SUMMARY Several systems-level datasets designed to dissect host-pathogen interactions during influenza A infection have been reported. However, apparent discordance among these data has hampered their full utility toward advancing mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we performed a meta-analysis of data from eight published RNAi screens and integrated these data with three protein interaction datasets, including one generated within the context of this study. Further integration of these data with global virus-host interaction analyses revealed a functionally validated biochemical landscape of the influenza-host interface, which can be queried through a simplified and customizable web portal (http://www.metascape.org/IAV). Follow-up studies revealed that the putative ubiquitin ligase UBR4 associates with the viral M2 protein and promotes apical transport of viral proteins. Taken together, the integrative analysis of influenza OMICs datasets illuminates a viral-host network of high-confidence human proteins that are essential for influenza A virus replication.

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Section: Resultsmentioning

confidence: 99%

Meta- and Orthogonal Integration of Influenza “OMICs” Data Defines a Role for UBR4 in Virus Budding

Tripathi

Pohl

Zhou

et al. 2015

Cell Host & Microbe

832

724

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“…HMGR and lanosterol levels are inversely correlated, with excess HMGR being degraded by the ERAD pathway (Hampton and Garza, 2009). Pathogen-specific events can also control protein levels in the ER: the US2, US3 and US11 glycoproteins encoded by human cytomegalovirus (HCMV) co-opt the ERAD pathway to degrade Class I MHC heavy chains (Morito and Nagata, 2015). Our findings suggest a new layer of homeostatic control, in which ERAD activity itself is regulated by controlling the levels of select components through the action of UBC6e.…”

Section: Discussionmentioning

confidence: 99%

Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e

et al. 2016

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Endoplasmic reticulum-associated degradation (ERAD) is essential for protein quality control in the ER, not only when the ER is stressed, but also at steady state. We report a new layer of homeostatic control, in which ERAD activity itself is regulated post-transcriptionally and independently of the unfolded protein response by adjusting the endogenous levels of EDEM1, OS-9 and SEL1L (ERAD enhancers). Functional UBC6e requires its precise location in the ER to form a supramolecular complex with Derlin2. This complex targets ERAD enhancers for degradation, a function that depends on UBC6e's enzymatic activity. Ablation of UBC6e causes up-regulation of active ERAD enhancers and so increases clearance not only of terminally misfolded substrates, but also of wild-type glycoproteins that fold comparatively slowly in vitro and in vivo. The levels of proteins that comprise the ERAD machinery are thus carefully tuned and adjusted to prevailing needs.

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“…It represents an efficient and fast strategy developed by cells to decrease the ER lumen overflow by unfolded, misfolded, or damaged proteins. Since this pathway is not this dissertation’s main topic, it will be not described further [for more details, we suggest the following publications (18, 19)].…”

Section: Er Stress Induction and Unfolded Protein Response (Upr)mentioning

confidence: 99%

Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate

et al. 2017

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Perturbation of endoplasmic reticulum (ER) homeostasis results in a stress condition termed “ER stress” determining the activation of a finely regulated program defined as unfolded protein response (UPR) and whose primary aim is to restore this organelle’s physiological activity. Several physiological and pathological stimuli deregulate normal ER activity causing UPR activation, such as hypoxia, glucose shortage, genome instability, and cytotoxic compounds administration. Some of these stimuli are frequently observed during uncontrolled proliferation of transformed cells, resulting in tumor core formation and stage progression. Therefore, it is not surprising that ER stress is usually induced during solid tumor development and stage progression, becoming an hallmark of such malignancies. Several UPR components are in fact deregulated in different tumor types, and accumulating data indicate their active involvement in tumor development/progression. However, although the UPR program is primarily a pro-survival process, sustained and/or prolonged stress may result in cell death induction. Therefore, understanding the mechanism(s) regulating the cell survival/death decision under ER stress condition may be crucial in order to specifically target tumor cells and possibly circumvent or overcome tumor resistance to therapies. In this review, we discuss the role played by the UPR program in tumor initiation, progression and resistance to therapy, highlighting the recent advances that have improved our understanding of the molecular mechanisms that regulate the survival/death switch.

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Pathogenic Hijacking of ER-Associated Degradation: Is ERAD Flexible?

Cited by 50 publications

References 98 publications

Meta- and Orthogonal Integration of Influenza “OMICs” Data Defines a Role for UBR4 in Virus Budding

Meta- and Orthogonal Integration of Influenza “OMICs” Data Defines a Role for UBR4 in Virus Budding

Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e

Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate

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