Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion
Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion
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DOI：
10.15252/embr.201643504
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Lihrmann, Isabelle
中科院分区：
文献类型：
--
作者：
Hamieh, Abdallah;Cartier, Dorthe;Lihrmann, Isabelle
硒蛋白T （Selenoprotein T, SeIT）是最近发现的一种硫氧还蛋白样蛋白，在发育过程中表达非常高，但仅限于成年期的内分泌组织，其功能尚不清楚。我们在这里报道，在内分泌细胞中，SeIT是适应高激素水平产生的应激条件所必需的。利用免疫荧光和透射电镜免疫金方法，我们发现SeIT在所有激素分泌型垂体细胞的内质网膜上表达。促皮质细胞中SeIT的下调可促进未折叠蛋白反应（UPR）和内质网应激，降低内质网相关蛋白降解（ERAD）和激素产生。利用酵母中seit膜蛋白相互作用的筛选，我们对角化细胞相关蛋白2 （KCP2）进行了分类，KCP2是蛋白复合物寡糖转移酶（OST）的一个亚基。事实上，SeIT不仅与KCP2相互作用，还与a型OST复合物的其他亚基相互作用，这些亚基在SeIT敲除后被耗尽，导致POMC n -糖基化缺陷。本研究发现，SeIT是a型OST复合体的一个新的亚基，对其完整性和内质网稳态至关重要，并发挥关键的适应功能，使内分泌细胞能够适当地实现激素的成熟和分泌。
Selenoprotein T (SeIT) 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 SeIT 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 SeIT is expressed at the endoplasmic reticulum membrane in all hormone-producing pituitary cell types. SeIT 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 SeIT-membrane protein interactions, we sort keratinocyte-associated protein 2 (KCP2), a subunit of the protein complex oligosaccharyltransferase (OST). In fact, SeIT interacts not only with KCP2 but also with other subunits of the A-type OST complex which are depleted after SeIT knockdown leading to POMC N-glycosylation defects. This study identifies SeIT 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.