Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization.
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.
['Kanemoto|Soshi|S|', 'Kobayashi|Yasuhiro|Y|', 'Yamashita|Teruhito|T|', 'Miyamoto|Takeshi|T|', 'Cui|Min|M|', 'Asada|Rie|R|', 'Cui|Xiang|X|', 'Hino|Kenta|K|', 'Kaneko|Masayuki|M|', 'Takai|Tomoko|T|', 'Matsuhisa|Koji|K|', 'Takahashi|Naoyuki|N|', 'Imaizumi|Kazunori|K|']
D000818:Animals D001854:Bone Marrow Cells D002454:Cell Differentiation D017362:Cyclic AMP Response Element-Binding Protein D005786:Gene Expression Regulation D016173:Macrophage Colony-Stimulating Factor D008264:Macrophages D008297:Male D008565:Membrane Proteins D051379:Mice D008813:Mice, Inbred ICR D009419:Nerve Tissue Proteins D010010:Osteoclasts D055550:Protein Stability D021381:Protein Transport D053245:RANK Ligand
Osteoclastogenesis Transcription factor Endoplasmic reticulum Cell-cell fusion