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.
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan soshikanemoto@hiroshima-u.ac.jp imaizumi@hiroshima-u.ac.jp.
Soshi
S
Kanemoto
Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
Yasuhiro
Y
Kobayashi
Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
Teruhito
T
Yamashita
Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Takeshi
T
Miyamoto
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Min
M
Cui
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Rie
R
Asada
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Xiang
X
Cui
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Kenta
K
Hino
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Masayuki
M
Kaneko
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Tomoko
T
Takai
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Koji
K
Matsuhisa
Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
Naoyuki
N
Takahashi
Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan soshikanemoto@hiroshima-u.ac.jp imaizumi@hiroshima-u.ac.jp.
Kazunori
K
Imaizumi
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism
C116472:Creb3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C499636:DC-STAMP protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor
Cell-cell fusion; Endoplasmic reticulum; Osteoclastogenesis; Transcription factor