Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation

Lee, Jea Hwang; Park, Ki-Jun; Jang, Jun Ki; Jeon, Yeong Ha; Ko, Kwan Young; Kwon, Joon Hyun; Lee, Seung Rock; Kim, Ick Young

doi:10.1074/jbc.m115.680215

Cited by 72 publications

(69 citation statements)

References 52 publications

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“…ER membrane is known as a privileged site to recruit proteins into complexes, and several membrane‐bound selenoproteins like selenoproteins S, K, and N have been shown to be associated with protein complexes . In order to identify SelT interactants, we used a modified split‐ubiquitin system for in vivo detection of interactions between transmembrane proteins in yeast.…”

Section: Resultsmentioning

confidence: 99%

Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion

et al. 2017

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Selenoprotein T (SelT) is a recently characterized thioredoxin-like protein whose expression is very high during development, but is confined to endocrine tissues in adulthood where its function is unknown. We report here that SelT is required for adaptation to the stressful conditions of high hormone level production in endocrine cells. Using immunofluorescence and TEM immunogold approaches, we find that SelT is expressed at the endoplasmic reticulum membrane in all hormone-producing pituitary cell types. SelT knockdown in corticotrope cells promotes unfolded protein response (UPR) and ER stress and lowers endoplasmic reticulum-associated protein degradation (ERAD) and hormone production. Using a screen in yeast for SelT-membrane protein interactions, we sort keratinocyte-associated protein 2 (KCP2), a subunit of the protein complex oligosaccharyltransferase (OST). In fact, SelT interacts not only with KCP2 but also with other subunits of the A-type OST complex which are depleted after SelT knockdown leading to POMC N-glycosylation defects. This study identifies SelT as a novel subunit of the A-type OST complex, indispensable for its integrity and for ER homeostasis, and exerting a pivotal adaptive function that allows endocrine cells to properly achieve the maturation and secretion of hormones.

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Section: Resultsmentioning

confidence: 99%

Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion

et al. 2017

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“…Pharmacological blockade of thioredoxin reductases is thought to promote apoptosis by depletion of reduced thioredoxin 43, 44 , which is a direct negative regulator of ASK1 45 . We also identified multiple high-occupancy selenoprotein targets of acetaminophen (SELK, VIMP; Figures 4B and 5C and Table 1) that are critical components of the ER-associated degradation machinery 46, 47 , the perturbation of which can also lead to ASK1 activation 48 . Another negative regulator of ASK1 activation 49 PARK7, or DJ-1, was targeted by acetaminophen at a key active-site residue (Table 1) and has been recently characterized as a glutathione-independent glyoxalase/protein deglycase critical for oxidative stress resistance 50, 51 .…”

Section: Discussionmentioning

confidence: 99%

Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites

et al. 2017

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Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)cysteine residues throughout the liver proteome. Our findings thus provide an advanced experimental framework to characterize the proteomic reactivity of drug metabolites in vivo, revealing target profiles that may help to explain mechanisms and identify risk factors for drug-induced liver injury.

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“…The next selenoprotein related with the ER is selenoprotein S, which, by cooperation with another membrane protein (valozin-containing protein), provides the incorporation of selenoprotein K into the ER. The main evidence of this is that interaction between selenoprotein K and valozin-containing protein does not occur in cells deprived of selenoprotein S, while selenoprotein S interacts with valozin-containing protein, regardless of the presence or absence of selenoprotein K. Expression of selenoprotein S and K rises according to stress of the ER (Lee et al, 2015).…”

Section: Selenoproteins Of the Endoplasmic Reticulum Lumenmentioning

confidence: 99%

Modern concept of biological identification of selenoproteins

Stanishevska

2018

Regul. Mech. Biosyst.

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Humans possess 25 selenoproteins, approximately half of which are enzymes (selenoenzymes) required for preventing, regulating, or reversing oxidative damage, while others participate in providing calcium metabolism, thyroid hormone maintenance, protein synthesis, cytoskeletal structure etc. This review examines the latest evidences of the biological effects of selenoproteins according to the method of complex analysis of the material. Selenoprotein P promotes insulin resistance in type 2 diabetes, mediates myocardial ischemic-reperfusion injuries and provides protection against disease by reducing chronic oxidative stress. Selenoprotein T is expressed at the endoplasmic reticulum membrane in all cells during development, but is confined to endocrine tissues in adulthood, controls homeostasis of glucose and prevents neurodegeneration by reducing oxidative stress factors. Expression of selenoprotein K is required for efficient Ca2+ flux into melanoma cancer cells, tumour growth and metastasic potential depend on SelK but it suppresses human choriocarcinoma cells. SelK also serves to maintain the normal physiological functions of skeletal muscle. Selenoprotein N deficiency, caused by mutations in the human gene, promotes myopathy characterized by muscle weakness, spinal rigidity, respiratory insufficiency. Sel N participates in normal physiology of skeletal and smooth muscle tissues. Selenoprotein M is located in the endoplasmic reticulum, characterized by high expression in the brain, antioxidative, neuroprotective activity and regulates intracellular Ca2+ levels. Also, the overexpression of SelM was detected in human hepatocellular carcinoma. Selenoprotein S is mentioned as a regulator of ER stress and inflammatory processes. Selenoprotein F controls cell proliferation by the impact on G1period of the cell cycle. Moreover, it is implicated in the pathogenesis of some types of cancer. The Sel F deficiency reduces the migration and invasive ability of the cells. Knockdown of selenoprotein W in rodents leads to increased release of Ca2+, causes oxidative ultramicroscopic injuries of the endoplasmic reticulum and mitochondria ultrastructure, which in turn increases the levels of inflammatory factors. Selenoprotein H is involved in redox regulation, in tumourogenesis. Knockdown of selenoprotein H decreases cellular differentiation and increases proliferation and migration of cells. Selenoproteins U, V, I, O, R are recently identified and their functions are not clearly known. The data analyzed in the review help determine promising directions in the study of the selenoproteins.

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Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation

Cited by 72 publications

References 52 publications

Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion

Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion

Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites

Modern concept of biological identification of selenoproteins

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