No abstract

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...

Pterygium is a common ophthalmic disease affecting humans only. Extensive epidemiological data have demonstrated a causative effect of chronic ultraviolet (UV) radiation on pterygia. Progress has been made in determining the origin of pterygia, their nasal predilection and wing‑shaped appearance, and the roles of UV radiation in the initiation and the development of pterygia. In the present review, the current understanding of the involvement of UV radiation in the pathogenesis of pterygia is summarized. This involvement includes the alteration of limbal stem cells and fibroblasts that contribute to the initiation of pterygia and the induction of various pro‑inflammatory cytokines, growth factors and matrix metalloproteinases that promote the progression of pterygia. Further elucidation of the roles of UV radiation in the pathogenesis of pterygia may help to encourage individuals at risk of developing pterygia to take preventive measures and aid researchers in the development of novel targeted therapeutic agents to treat pterygia.

These findings suggest that H(2)O(2) at low levels promotes cell adhesion, migration, and wound healing in cornea cells or tissue, and the interaction of H(2)O(2) with Src plays a major role.