Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117596, Singapore.
Sci Adv. 2020 Jul 31;6(31). doi: 10.1126/sciadv.abb2497. Print 2020 Jul.
ELKS1 is a protein with proposed roles in regulated exocytosis in neurons and nuclear factor κB (NF-κB) signaling in cancer cells. However, how these two potential roles come together under physiological settings remain unknown. Since both regulated exocytosis and NF-κB signaling are determinants of mast cell (MC) functions, we generated mice lacking ELKS1 in connective tissue MCs (-Cre) and found that while ELKS1 is dispensable for NF-κB-mediated cytokine production, it is essential for MC degranulation both in vivo and in vitro. Impaired degranulation was caused by reduced transcription of Syntaxin 4 (STX4) and Syntaxin binding protein 2 (Stxpb2), resulting from a lack of ELKS1-mediated stabilization of lysine-specific demethylase 2B (Kdm2b), which is an essential regulator of STX4 and Stxbp2 transcription. These results suggest a transcriptional role for active-zone proteins like ELKS1 and suggest that they may regulate exocytosis through a novel mechanism involving transcription of key exocytosis proteins.
ELKS1 是一种蛋白，其在神经元中具有调节性胞吐作用的作用，在癌细胞中具有核因子 κB（NF-κB）信号的作用。然而，在生理环境下，这两种潜在作用如何结合在一起尚不清楚。由于调节性胞吐和 NF-κB 信号都是肥大细胞（MC）功能的决定因素，我们生成了结缔组织 MC 中缺乏 ELKS1 的小鼠（-Cre），并发现虽然 ELKS1 对于 NF-κB 介导的细胞因子产生是可有可无的，但它对于体内和体外的 MC 脱颗粒都是必不可少的。脱颗粒受损是由于 STX4 和 Stxbp2 的转录减少所致，这是由于缺乏 ELKS1 介导的赖氨酸特异性去甲基酶 2B（Kdm2b）的稳定，而 Kdm2b 是 STX4 和 Stxbp2 转录的关键调节因子。这些结果表明，活性区蛋白（如 ELKS1）具有转录作用，并表明它们可能通过一种涉及关键胞吐蛋白转录的新机制来调节胞吐作用。
