Role of Selenof as a Gatekeeper of Secreted Disulfide-Rich Glycoproteins

Yim, Sun Hee; Everley, Robert A.; Schildberg, Frank A.; Lee, Sang Goo; Orsi, Andrea; Barbati, Zachary R.; Karatepe, Kutay; Fomenko, Dmitry E.; Tsuji, Petra A.; Luo, Hongbo; Gygi, Steven P.; Sitia, Roberto; Sharpe, Arlene H.; Hatfield, Dolph L.; Gladyshev, Vadim N.

doi:10.1016/j.celrep.2018.04.009

Cited by 54 publications

(37 citation statements)

References 46 publications

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“…A small study in humans showed a positive effect on antibody titers against the diphtheria vaccine with selenium supplementation that correspond to increased lymphocyte counts [ 104 ]. In a more recent study involving Selenoprotein F (SELENOF) knockout mice, elevated levels of immunoglobulins were detected in the sera that were nonfunctional [ 38 ]. The authors of this study concluded that SELENOF functions as a gatekeeper of immunoglobulins in the endoplasmic reticulum (ER), which supports the redox quality control of these proteins and likely other proteins.…”

Section: Leukocyte Functionsmentioning

confidence: 99%

Selenium, Selenoproteins, and Immunity

2018

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Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.

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Section: Leukocyte Functionsmentioning

confidence: 99%

Selenium, Selenoproteins, and Immunity

2018

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“…In vitro, Sep15 has been shown to increase the enzymatic activity of UGGT1/2 [83]. Sep15 may modulate the selection of substrates by UGGT or act upon substrates modified by UGGT to help with their repair and folding [86]. Selenocysteines, considered the 21 st amino acid, are found in the active site of Sep15.…”

Section: Carbohydrate-dependent Protein Quality Controlmentioning

confidence: 99%

Protein Quality Control in the Endoplasmic Reticulum

2019

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The site of protein folding and maturation for the majority of proteins that are secreted, localized to the plasma membrane or targeted to endomembrane compartments is the endoplasmic reticulum (ER). It is essential that proteins targeted to the ER are properly folded in order to carry out their function, as well as maintain protein homeostasis, as accumulation of misfolded proteins could lead to the formation of cytotoxic aggregates. Because protein folding is an error-prone process, the ER contains protein quality control networks that act to optimize proper folding and trafficking of client proteins. If a protein is unable to reach its native state, it is targeted for ER retention and subsequent degradation. The protein quality control networks of the ER that oversee this evaluation or interrogation process that decides the fate of maturing nascent chains is comprised of three general types of families: the classical chaperones, the carbohydrate-dependent system, and the thiol-dependent system. The cooperative action of these families promotes protein quality control and protein homeostasis in the ER. This review will describe the families of the ER protein quality control network and discuss the functions of individual members.

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“…These domains of UGGT do not carry a catalytic site, and therefore lack a direct role in disulfide bond formation, but expose hydrophobic stretches for recognition of unfolded glycoproteins [ 58 ]. UGGT associates with a small selenoprotein, Sep15, also called Selenof [ 59 ]. Sep15 contains a catalytically active thioredoxin-like domain, implying that it may have a role in oxidoreductase activity on the glycoprotein substrate.…”

Section: Oxidoreductases Associated With the Glycoprotein Folding mentioning

confidence: 99%

“…The exact function of Sep15 is unknown, but its association with UGGT indicates its possible role in either modulating UGGT enzyme activity or assessing the disulfide bonds of the UGGT substrates. Sep15 knockout mice showed increased levels of secreted non-functional immunoglobulins, suggesting that it might function as a quality control gatekeeper for misfolded glycoproteins [ 59 ].…”

Section: Oxidoreductases Associated With the Glycoprotein Folding mentioning

confidence: 99%

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Patel

Saad

Shenkman

et al. 2020

Cells

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N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.

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Role of Selenof as a Gatekeeper of Secreted Disulfide-Rich Glycoproteins

Cited by 54 publications

References 46 publications

Selenium, Selenoproteins, and Immunity

Selenium, Selenoproteins, and Immunity

Protein Quality Control in the Endoplasmic Reticulum

Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

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