The Sep15 protein family: Roles in disulfide bond formation and quality control in the endoplasmic reticulum

Labunskyy, Vyacheslav M.; Hatfield, Dolph L.; Gladyshev, Vadim N.

doi:10.1080/15216540601126694

Cited by 112 publications

(80 citation statements)

References 29 publications

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“…The presence of a thioredoxinlike fold and the association of Sep15 with UGGT suggests that Sep15 might have roles in disulfide bond formation and quality control of a restricted group of glycoproteins serving as UGGT substrates (197). Consistent with its function in protein folding, Sep15 expression is induced by conditions that are associated with accumulation of misfolded proteins in the ER (199).…”

Section: H the 15-kda Selenoprotein And Selenoprotein Mmentioning

confidence: 52%

“…This flexible region may plausibly participate in substrate binding or interaction with other protein factors. Collectively, the presence of redox-active motifs and structural similarities to other thioredoxin-fold oxidoreductases suggest that Sep15 and SelM may catalyze the reduction or rearrangement of disulfide bonds in the ER-localized or secretory proteins (197).…”

Section: H the 15-kda Selenoprotein And Selenoprotein Mmentioning

confidence: 99%

See 1 more Smart Citation

Selenoproteins: Molecular Pathways and Physiological Roles

Labunskyy

Hatfield

Gladyshev³

2014

Physiological Reviews

983

784

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Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a seleniumcontaining amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

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Section: H the 15-kda Selenoprotein And Selenoprotein Mmentioning

confidence: 52%

Section: H the 15-kda Selenoprotein And Selenoprotein Mmentioning

confidence: 99%

Selenoproteins: Molecular Pathways and Physiological Roles

Labunskyy

Hatfield

Gladyshev³

2014

Physiological Reviews

983

784

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“…Analysis of Sep15 KO Mice for Prostate and Brain PathologiesSep15 is expressed at elevated levels in prostate, liver, kidney, testis, and brain (25). At the same time, Sep15 expression is decreased in malignant prostate cell lines and in hepatocarcinoma.…”

Section: Absence Of Sep15 Does Not Affect Expression Of Other Selenopmentioning

confidence: 99%

Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice

Kasaikina

Fomenko

Labunskyy

et al. 2011

Journal of Biological Chemistry

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The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteinerich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency.Selenium (Se) is a trace element that plays a role in immune function, reducing cancer incidence, and redox homeostasis in mammals (1-3). Se is primarily used in the form of selenocysteine, known as the 21 st amino acid, which is encoded by UGA codon and located in the active sites of oxidoreductases (4, 5).The 15-kDa selenoprotein (Sep15) was identified in mammals 13 years ago as a protein of unknown function (6). The NMR structure of the Drosophila melanogaster Sep15 revealed a thioredoxin-like fold within its oxidoreductase domain, with selenocysteine (Sec) 2 located in the predicted catalytic position (7). Previous studies showed that Sep15 resides in the endoplasmic reticulum (ER) and interacts with UDP-glucose:glycoprotein glucosyltransferase (UGT) (8). The latter protein is a part of the calnexin-calreticulin glycoprotein folding cycle and is known to be responsible for targeting unfolded glycoproteins for calcium-dependent transient glucosylation. Sep15 contains the ER targeting peptide, but lacks an ER retention signal. The tight binding to UGT allows retention of Sep15 in the ER. These findings suggested that Sep15 may assist UGT function and control folding or secretion of certain glycoproteins.Recently, Sep15 was found to be regulated by ER stress. Sep15 expression was up-regulated in response to adaptive ER stress caused by tunicamycin and brefeldin A. At the same time, more robust ER stress caused by DTT and thapsigargin treatments induced rapid proteasomal degradation of Sep15 (9). Presumably, disruption of Sep15-UGT interaction because of reduction of disulfide bonds in the Sep15 UGT-binding domain displaced Sep15 from the ER. Expression of Sep15 is higher in tissues with secretory functions, such as l...

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“…The most intriguing case was that of glycoproteins in the third class, as they showed a prolonged association with CNX/CRT. It was speculated that the observed results could be due to a protein-protein association between the lectins and glycoproteins or, alternatively, to the fact that a selenocysteine-containing oxidoreductase (Sep15) that forms a 1:1 complex with GT could play a role in assessing and refining the disulfide bond content of glycoproteins in this class (18,19).…”

Section: What Happens Once Glycoproteins Are In Cnx/crt Cycles?mentioning

confidence: 99%

Getting In and Out from Calnexin/Calreticulin Cycles

Caramelo

Parodi

2008

Journal of Biological Chemistry

266

229

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The N-glycan-dependent quality control mechanism of glycoprotein folding was proposed initially by Helenius and coworkers several years ago; with a few minor modifications, it is still valid today ( Fig. 1) (1-3).2 Glycan processing starts immediately after its transfer from a dolichol-P-P derivative to Asn residues in nascent polypeptide chains entering the lumen of the ER. 3 Removal of the outermost and following glucoses by the successive action of GI and GII exposes the Glc 1 Man 9 GlcNAc 2 epitope (Fig. 2). This structure is then recognized by two ER resident lectins (CNX and CRT) that specifically bind monoglucosylated polymannose glycans. This is followed by removal of the innermost glucose by GII, thus liberating the glycoprotein from the lectin anchor. The proteinlinked glycan is then reglucosylated by the soluble ER enzyme GT only if the protein moiety displays non-native three-dimensional structures, as this enzyme behaves as a conformational sensor. Cycles of CNX/CRT-glycoprotein binding and liberation, catalyzed by the opposing activities of GT and GII, are terminated once glycoproteins attain their native structures. Glucose-free glycoproteins then continue their transit through the secretory pathway. Alternatively, permanently misfolded glycoproteins may be then transported to the cytosol for proteasomal degradation. Lectin-glycoprotein association not only thwarts Golgi exit of folding intermediates and irreparably misfolded glycoproteins but also enhances folding efficiency by preventing aggregation and promoting proper disulfide bonding. The latter is catalyzed by an oxidoreductase of the proteindisulfide isomerase family (ERp57) that acts exclusively on glycoproteins, as it is loosely associated with CNX/CRT.GT is the only component of the quality control mechanism that senses protein conformations, as it recognizes hydrophobic amino acid patches exposed in molten globule-like conformers (4, 5). GT may also glucosylate glycoproteins in not fully assembled oligomeric complexes because it also recognizes hydrophobic surfaces exposed as a consequence of the absence of subunit components (6). The aim of this review is to give an overview of recent reports dealing with the entrance and exit of glycoproteins from CNX/CRT cycles. Getting In: GII Is Not What It Was Thought to BeThe first step in the pathway leading to the entrance of glycoproteins into CNX/CRT cycles is the removal of the outermost glucose unit from the glycan by the membrane enzyme GI. This reaction occurs almost simultaneously with glycan transfer. The rapid GI-mediated deglucosylation of the protein-linked glycan, as well as the apparent inability of the enzyme to remove in vivo (but not in vitro) the glucose from the dolichol-P-P-linked glycan, strongly suggests the existence of a supercomplex formed by the oligosaccharyltransferase, GI, and the dolichol derivative, with a very precise orientation of the components.It was assumed that the sole role of GII was that of removing glucose residues l and n (Fig. 2). Recent work has sugg...

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The Sep15 protein family: Roles in disulfide bond formation and quality control in the endoplasmic reticulum

Cited by 112 publications

References 29 publications

Selenoproteins: Molecular Pathways and Physiological Roles

Selenoproteins: Molecular Pathways and Physiological Roles

Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice

Getting In and Out from Calnexin/Calreticulin Cycles

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