TY - JOUR
T1 - Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization
AU - Kanemoto, Soshi
AU - Kobayashi, Yasuhiro
AU - Yamashita, Teruhito
AU - Miyamoto, Takeshi
AU - Cui, Min
AU - Asada, Rie
AU - Cui, Xiang
AU - Hino, Kenta
AU - Kaneko, Masayuki
AU - Takai, Tomoko
AU - Matsuhisa, Koji
AU - Takahashi, Naoyuki
AU - Imaizumi, Kazunori
N1 - Publisher Copyright:
© 2015. Published by The Company of Biologists Ltd.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1242/jcs.176057
DO - 10.1242/jcs.176057
M3 - Article
C2 - 26503158
AN - SCOPUS:84949920854
VL - 128
SP - 4353
EP - 4365
JO - The Quarterly journal of microscopical science
JF - The Quarterly journal of microscopical science
SN - 0021-9533
IS - 23
ER -