Department of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, Hawaii, USA.
Department of Cell and Molecular Biology, Medical Microbiolgy, and Pharmacology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Antioxid Redox Signal. 2021 Oct 1;35(10):775-787. doi: 10.1089/ars.2018.7594. Epub 2019 Mar 6.
Selenoproteins are an essential class of proteins involved in redox signaling and energy metabolism. However, the functions of many selenoproteins are not clearly established. Selenoprotein M (SELENOM), an endoplasmic reticulum (ER)-resident oxidoreductase bearing structural similarity to thioredoxin (TXN), is among those yet to be fully characterized. This protein is highly expressed in hypothalamic regions involved in leptin signaling and has been previously linked to energy metabolism. Herein, we performed a series of studies using and models to probe the specific influence of SELENOM on hypothalamic leptin signaling and assess SELENOM-regulated pathways. Our initial experiment demonstrated that (i) leptin promotes hypothalamic expression of SELENOM and (ii) leptin-induced STAT3 phosphorylation is impeded by SELENOM deficiency. Additional studies using mHypoE-44 immortalized hypothalamic neurons corroborated these findings, as SELENOM deficiency obstructed downstream STAT3 phosphorylation and cytosolic calcium responses evoked by leptin treatment. Correspondingly, SELENOM overexpression enhanced leptin sensitivity. Microarray analysis conducted in parallel on hypothalamic tissue and mHypoE-44 cells revealed multiple genes significantly affected by SELENOM deficiency, including thioredoxin interacting protein, a negative regulator of the TXN system. Further analysis determined that (i) SELENOM itself possesses intrinsic TXN activity and (ii) SELENOM deficiency leads to a reduction in overall TXN activity. Finally, mHypoE-44 cells lacking SELENOM displayed diminished activation of the nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) signaling pathway and increased susceptibility to ER stress-mediated cell death. In sum, these findings establish SELENOM as a positive regulator of leptin signaling and TXN antioxidant activity in the hypothalamus. 35, 775-787.
硒蛋白是一类参与氧化还原信号和能量代谢的必需蛋白。然而，许多硒蛋白的功能尚未完全确定。SELENOM（硒蛋白 M）是一种内质网（ER）驻留的氧化还原酶，具有与硫氧还蛋白（TXN）相似的结构，是尚未完全表征的蛋白之一。这种蛋白在涉及瘦素信号的下丘脑区域高度表达，先前与能量代谢有关。在此，我们使用 和 模型进行了一系列研究，以探究 SELENOM 对下丘脑瘦素信号的具体影响，并评估 SELENOM 调节的途径。我们的初步实验表明：（i）瘦素促进下丘脑 SELENOM 的表达；（ii）SELENOM 缺乏会阻碍瘦素诱导的 STAT3 磷酸化。使用 mHypoE-44 永生化下丘脑神经元进行的额外研究证实了这些发现，因为 SELENOM 缺乏会阻碍瘦素处理引起的下游 STAT3 磷酸化和细胞质钙反应。相应地，SELENOM 过表达增强了瘦素的敏感性。在同时进行的下丘脑组织和 mHypoE-44 细胞的微阵列分析揭示了多个受 SELENOM 缺乏显著影响的基因，包括硫氧还蛋白相互作用蛋白，这是 TXN 系统的负调节剂。进一步的分析确定：（i）SELENOM 本身具有内在的 TXN 活性；（ii）SELENOM 缺乏会导致整体 TXN 活性降低。最后，缺乏 SELENOM 的 mHypoE-44 细胞显示核因子 kappa-轻链增强子的激活 B 细胞（NF-κB）信号通路的激活减少和对 ER 应激介导的细胞死亡的敏感性增加。总之，这些发现确立了 SELENOM 作为下丘脑瘦素信号和 TXN 抗氧化活性的正调节剂。35, 775-787。
