Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization

• Published in: Journal of cell science Vol. 128; no. 23; pp. 4353 - 4365
• Main Authors: Kanemoto, Soshi, Kobayashi, Yasuhiro, Yamashita, Teruhito, Miyamoto, Takeshi, Cui, Min, Asada, Rie, Cui, Xiang, Hino, Kenta, Kaneko, Masayuki, Takai, Tomoko, Matsuhisa, Koji, Takahashi, Naoyuki, Imaizumi, Kazunori
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists 01.12.2015
• Subjects: Animals; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cell Differentiation; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Gene Expression Regulation; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - metabolism; Macrophages - cytology; Macrophages - metabolism; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred ICR; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Osteoclasts - cytology; Osteoclasts - metabolism; Protein Stability; Protein Transport; RANK Ligand - genetics; RANK Ligand - metabolism; Osteoclastogenesis; Cell-cell fusion; Transcription factor; Endoplasmic reticulum
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.176057

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.