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

Abstract

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.

A selenoprotein T‐derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress

“…The ontogenetic expression pattern of SelT in heart is similar to that observed in the brain and other organs, such as kidney, liver, lung, skeletal muscle and adrenal gland. In fact, SelT expression is drastically reduced after cell differentiation in most tissues, as observed in chromaffin cells and Purkinje cells . In contrast, its expression is maintained in several adult endocrine tissues, such as pituitary, thyroid or testis, and is highly induced in metabolically active proliferating cells and in cells that are endowed with some plasticity and regenerative capacity .…”

“…In particular, selenoprotein T (SelT or SELENOT) is a key thioredoxin‐like enzyme present in the endoplasmic reticulum, which is essential at early stage of mouse development . SelT is highly expressed in most embryonic organs, but declines gradually as the organs develop, to disappear in most adult tissues except the endocrine glands . Targeted inactivation of SelT in pancreatic β‐cells resulted in a reduction in pancreatic islet size and impaired glucose tolerance, thus indicating a possible defect in cell commitment to β‐cell lineage.…”

“…Several selenoproteins are highly expressed during development, [13][14][15] and their loss has been associated with major anatomical alterations and functional defects in rodents. 16,17 In particular, selenoprotein T (SelT or SELE-NOT) is a key thioredoxin-like enzyme present in the endoplasmic reticulum, 18,19 which is essential at early stage of mouse development. 20,21 SelT is highly expressed in most embryonic organs, but declines gradually as the organs develop, to disappear in most adult tissues except the endocrine glands.…”

“…20,21 SelT is highly expressed in most embryonic organs, but declines gradually as the organs develop, to disappear in most adult tissues except the endocrine glands. 15,19,22 Targeted inactivation of SelT in pancreatic b-cells resulted in a reduction in pancreatic islet size and impaired glucose tolerance, thus indicating a possible defect in cell commitment to b-cell lineage. Similarly, SelT depletion in other neuroendocrine and endocrine cells provoked Ca 2+ store depletion, ER stress, misfolded protein accumulation and hormone production and secretion defects.…”

“…Similarly, SelT depletion in other neuroendocrine and endocrine cells provoked Ca 2+ store depletion, ER stress, misfolded protein accumulation and hormone production and secretion defects. 18,19 Although a large body of evidence has now accumulated showing that SelT affects the survival, differentiation and function of nervous and endocrine cells [18][19][20][21][22] via its redox activity, nothing is known about the expression and function of SelT in other vital tissues such as the heart, a tissue which is highly exposed to oxidative stress in particular after ischaemia/reperfusion (I/R). This study was undertaken to elucidate: (i) the expression of SelT during rat heart ontogenesis and after ex vivo induced ischaemia in adult rat heart, (ii) whether the exogenously administrated SelT-derived peptide SelT43-52 (PSELT), which encompasses the active redox site CXXSec is able to protect the heart in pharmacological post-conditioning after I/ R damage and (iii) the underlying intracellular mechanisms activated by PSELT to confer cardioprotection.…”