Selenoproteins in the secretorypathway
The ER-resident selenoproteins contribute to the redox environment of the lumen, because selenocysteine (Sec;or U in one letter code) is even more oxidizing than cysteine. However, the impact of Sec is difficult to measure directly because of the unusual way that it is incorporated into the selenoprotein. Sec is encoded by UGA, which is normally a stop codon. A special tRNA, tRNASec, reads UGA in the context of a cis-acting selenocysteine insertion sequence in the 3´UTR of the mRNA. The tRNASec is first charged with serine by seryl-tRNA ligase, the serine residue is then converted to a selenocysteine-residue by selenocysteine synthase and finally, the dedicated eukaryotic elongation factor mSelB/eEFSec binds to the tRNASec in a multiprotein complex at the ribosome [69].
Consequently, selenoprotein studies often have to make do with cysteine-substituted selenoproteins, which will underestimate the oxidizing power of the system.There are up to seven mammalian selenoproteins that are localized to the ER/secretory pathway, of which four will be considered briefly here:
SELENOF(Sep15),
SELENOS (SelS/VIMP),
SELENOP (SelP)and
SELENON (SelN) [70,71].
SELENOF is a widely expressed 15-kDa ER selenoprotein with a quality control function [72]. SELENOF is retained in the ER through interaction with the folding sensor UDP-glucose:Glycoprotein Glucosyltransferase (GT) via its cysteine-rich domain [73]. GT interacts with the innermost N-acetylglucosamine of misfolded glycoproteins, which should normally be buried, and monoglucosy-lates them, facilitating their return to the calnexin/cal-reticulin cycle. Based on the phenotype of SELENOF-deficient mice, which have an increase (rather than decrease) in nonfunctional circulating antibodies, the protein has been suggested to act as the gatekeeper of ER-to-Golgi transport for a subset of secretory glycoproteins [74]. Structural data suggest that SELENOF is an ER disulphide (or sulphide–selenide) isomerase/oxidoreductase and it is estimated to have a redox potentialo f 225 mV, consistent with that of a reductase [72].However, since the exact redox function of SELENOF is not known, it remains to be established whether native, selenium-loaded SELENOF is regulated by other electron donors (e.g. PDI) or electron acceptor s(e.g. Ero1a) or works alongside them to drive disul-phide bond reduction reactions.
SELENOS operates downstream of SELENOF, as a component of the ERAD machinery [75] and has an overall antioxidant capacity, at leastin vitro.The precise function of the SELENOS selenium moiety in ERAD is unknown, but one possibility is that it is required for the unfolding of misoxidized proteins prior to their retrotranslocation from the ER to the cytosol.
https://www.sciencedirect.com/science/article/pii/S2589004220301541
Tuore artikkeli, josaa ilmenee KELCH domaanit omaava proteiini ja CUL5 - ubikitinaatio säätelemässä SELENOS proteiinia.
Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding
Fumihiko Okumura
YuhaFujiki
https://doi.org/10.1016/j.isci.2020.100970Get rights and content
Under a Creative Commons license
The SELENOP selenoprotein has up to 10 Sec residues per protein, and is the major source, and a likely carrier, of selenocysteine in the body, with a role in antioxidant defence [76]. SELENOP is folded in the ER, requires glycosylation and possesses both sulphide-selenide and disulphide bonds. Only one of the SELENOP Sec residues is in a CxxU motif. Two other Sec-Cys bonds have been proposed for the C terminus (of the rat protein) and two disulphides have been detected by mass spectrometry between C149–C167and C153–C156. How spurious selenide–sulphide(S-Se) bonds are corrected or avoided (between the 10 SELENOP Sec residues and the 16 Cys residues) during folding of SELENOP in the ER is not known, and poses a thought-provoking question for redox-dependent protein quality control.
Of the secretory pathway selenoproteins, SELENON is perhaps the most puzzling because of its association with a form of muscular dystrophy called SEPN1-related muscular dystrophy. Patients with this disease have axial muscle weakness, scoliosis and spinal rigidity with variable skeletal muscle pathology. Curiously, SELENON is a widely expressed selenoprotein but is associated quite specifically with myotubule formation [77]. The reason why SELENON mutations give such a restricted phenotype is unclear, but may be due to dysregulation of calcium homeostasis by SELENON, increased sensitivity of myotubes to oxidative/nitrosative stress, or induction of the ER stress response, similar to that suggested for the disruptive role of PDI in neurodegenerative/Cole–Carpenter diseases, and ATP7B inWilson’s disease. Predicting and understanding how such disparate mutations can cause unusual disease phenotypes remain major challenges for the field. Despite much knowledge of the molecular details of ER quality control (ERQC) , disulphide bond formation and redox homeostasis, the picture remains incomplete.. "
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