Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization.
Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization.
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DOI：
10.1242/jcs.176057
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发表时间：
2015-12-01
影响因子：
4
通讯作者：
Imaizumi K
中科院分区：
文献类型：
--
作者：
Kanemoto S;Kobayashi Y;Yamashita T;Miyamoto T;Cui M;Asada R;Cui X;Hino K;Kaneko M;Takai T;Matsuhisa K;Takahashi N;Imaizumi K
Luman(也称为CREB3)是一种属于绿洲家族的II型跨膜转录因子，在正常情况下定位于内质网(ER)膜。作为对内质网胁迫的响应，OASIS家族成员经历了调控的膜内蛋白分解(RIP)，随后被切割的N-末端片段移位到细胞核。在本研究中，我们发现，用巨噬细胞集落刺激因子(M-CSF)和RANKL(也称为TNFSF11)处理骨髓巨噬细胞(BMMS)会引起Luman表达的时间依赖性增加，并且Luman在破骨细胞分化过程中经历RIP并被激活。在BMMS中，小发夹(Sh)RNA介导的Luman基因敲除阻止了多核破骨细胞的形成，同时伴随着DC-STAMP的抑制，DC-STAMP是破骨细胞发生过程中细胞-细胞融合所必需的。Luman的N末端促进DC-STAMP的启动子活性，导致DC-STAMP表达上调。此外，Luman与DC-STAMP相互作用，控制其稳定性和局部化。这些结果表明，鲁曼通过DC-STAMP诱导和破骨细胞形成过程中的细胞内分布，促进单核破骨细胞的细胞融合，从而调节破骨细胞的多核化。亮点文章：Luman是一种内质网驻留转录因子，通过在破骨细胞形成过程中通过DC-STAMP诱导和运输促进单核破骨细胞的细胞融合来调节破骨细胞的多核形成。
Luman (also known as CREB3) is a type-II transmembrane transcription factor belonging to the OASIS family that localizes to the endoplasmic reticulum (ER) membrane under normal conditions. In response to ER stress, OASIS-family members are subjected to regulated intramembrane proteolysis (RIP), following which the cleaved N-terminal fragments translocate to the nucleus. In this study, we show that treatment of bone marrow macrophages (BMMs) with cytokines – macrophage colony-stimulating factor (M-CSF) and RANKL (also known as TNFSF11) – causes a time-dependent increase in Luman expression, and that Luman undergoes RIP and becomes activated during osteoclast differentiation. Small hairpin (sh)RNA-mediated knockdown of Luman in BMMs prevented the formation of multinucleated osteoclasts, concomitant with the suppression of DC-STAMP, a protein that is essential for cell–cell fusion in osteoclastogenesis. The N-terminus of Luman facilitates promoter activity of DC-STAMP, resulting in upregulation of DC-STAMP expression. Furthermore, Luman interacts with DC-STAMP, and controls its stability and localization. These results suggest that Luman regulates the multinucleation of osteoclasts by promoting cell fusion of mononuclear osteoclasts through DC-STAMP induction and intracellular distribution during osteoclastogenesis. Highlighted Article: Luman, an ER-resident transcription factor, regulates the multinucleation of osteoclasts by promoting cell fusion of mononuclear osteoclasts through DC-STAMP induction and transportation during osteoclastogenesis.