Five Questions (with their Answers) on <scp>ER</scp>‐Associated Degradation

Pisoni, Giorgia Brambilla; Molinari, Maurizio

doi:10.1111/tra.12373

Cited by 36 publications

(17 citation statements)

References 104 publications

(126 reference statements)

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“…During unfolded protein response, ribosomal synthesis of the majority of proteins is blocked, the expression level of several ER luminal chaperones, such as BiP and Herp, is markedly increased to facilitate a correct folding of ER luminal polypeptides and, in the case of defective repair, misfolded proteins are degraded via a mechanism called the ER-associated protein degradation. 72 , 73 If the cell can finally cope with ER stress conditions, the expanded ER itself as well as the high amount of ER luminal chaperones have to be downsized to a physiological level again. Therefore, small vesicles bearing ER luminal and membrane chaperones are separated from the ER membrane, fuse with phagophores to build autophagosomes and finally are delivered to lysosomes for degradation—a process called autophagy ( Figure 2b ).…”

Section: Role Of Sec Proteins In Cellular Ca 2+ Homentioning

confidence: 99%

Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine

Linxweiler

Schick

Zimmermann

2017

Sig Transduct Target Ther

135

130

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The heterotrimeric Sec61 complex and the dimeric Sec62/Sec63 complex are located in the membrane of the human endoplasmic reticulum (ER) and play a central role in translocation of nascent and newly synthesized precursor polypeptides into the ER. This process involves targeting of the precursors to the membrane and opening of the polypeptide conducting Sec61 channel for translocation. Apart from this central role in the intracellular transport of polypeptides, several studies of the last decade uncovered additional functions of Sec proteins in intracellular signaling: Sec62 can induce ER-phagy in the process of recovery of cells from ER stress and the Sec61 channel can also act as a passive ER calcium leak channel. Furthermore, mutations, amplifications and an overexpression of the SEC genes were linked to various diseases including kidney and liver diseases, diabetes and human cancer. Studies of the last decade could not only elucidate the functional role of Sec proteins in the pathogenesis of these diseases, but also demonstrate a relevance of Sec62 as a prognostic and predictive biomarker in head and neck cancer, prostate and lung cancer including a basis for new therapeutic strategies. In this article, we review the current understanding of protein transport across the ER membrane as central function of Sec proteins and further focus on recent studies that gave first insights into the functional role and therapeutic relevance of Sec61, Sec62 and Sec63 in human diseases.

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Section: Role Of Sec Proteins In Cellular Ca 2+ Homentioning

confidence: 99%

Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine

Linxweiler

Schick

Zimmermann

2017

Sig Transduct Target Ther

135

130

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“…The ER-PQC is responsible for ensuring that proteins made in the ER are properly folded and correctly modified post-translationally, for example by glycosylation or disulfide bond formation, before they are permitted to the leave the ER on the way to their eventual target destinations(Walter and Ron 2011; Gardner et al 2013). Proteins that do not pass ER-PQC are not permitted to move on, and instead are translocated back out of the ER lumen and subjected to proteasome-mediated degradation in a process called ER associated degradation, or ERAD (Plemper and Wolf 1999; Pisoni and Molinari 2016) (Fig. 1E).…”

Section: Introductionmentioning

confidence: 99%

ER Protein Quality Control and the Unfolded Protein Response in the Heart

Arrieta

Blackwood

Glembotski

2017

Current Topics in Microbiology and Immunology

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Cardiac myocytes are the cells responsible for the robust ability of the heart to pump blood throughout the circulatory system. Cardiac myocytes grow in response to a variety of physiological and pathological conditions; this growth challenges endoplasmic reticulum-protein quality control (ER-PQC), a major feature of which includes the unfolded protein response (UPR). ER-PQC and the UPR in cardiac myocytes growing under physiological conditions, including normal development, exercise, and pregnancy, are sufficient to support hypertrophic growth of each cardiac myocyte. However, the ER-PQC and UPR are insufficient to respond to the challenge of cardiac myocyte growth under pathological conditions, including myocardial infarction and heart failure. In part, this insufficiency is due to a continual decline in the expression levels of important adaptive UPR components as a function of age and during myocardial pathology. This chapter will discuss the physiological and pathological conditions unique to the heart that involves ER-PQC, and whether the UPR is adaptive or maladaptive under these circumstances.

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“…One element of this network, termed ER-associated degradation (ERAD), is responsible for degrading misfolded secretory proteins that are marked by a polyubiquitin chain (Vembar and Brodsky, 2008; Hampton and Sommer, 2012; Olzmann et al. , 2013; Christianson and Ye, 2014; Pisoni and Molinari, 2016). Genetic mutation, errors in transcription or translation, or environmental stress can result in protein misfolding, which gives rise to various ERAD-associated diseases (Guerriero and Brodsky, 2012).…”

Section: Introductionmentioning

confidence: 99%