Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation.
Eukaryotic cells have signalling pathways from the endoplasmic reticulum (ER) to cytosol and nuclei, to avoid excess accumulation of unfolded proteins in the ER. We previously identified a new type of ER stress transducer, OASIS, a bZIP (basic leucine zipper) transcription factor, which is a member of the CREB/ATF family and has a transmembrane domain. OASIS is processed by regulated intramembrane proteolysis (RIP) in response to ER stress, and is highly expressed in osteoblasts. OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins. Here we identify the gene for type 1 collagen, Col1a1, as a target of OASIS, and demonstrate that OASIS activates the transcription of Col1a1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter region. Moreover, expression of OASIS in osteoblasts is induced by BMP2 (bone morphogenetic protein 2), the signalling of which is required for bone formation. Additionally, RIP of OASIS is accelerated by BMP2 signalling, which causes mild ER stress. Our studies show that OASIS is critical for bone formation through the transcription of Col1a1 and the secretion of bone matrix proteins, and they reveal a new mechanism by which ER stress-induced signalling mediates bone formation.
Murakami
Tomohiko
T
Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Saito
Atsushi
A
Hino
Shin-ichiro
S
Kondo
Shinichi
S
Kanemoto
Soshi
S
Chihara
Kazuyasu
K
Sekiya
Hiroshi
H
Tsumagari
Kenji
K
Ochiai
Kimiko
K
Yoshinaga
Kazuya
K
Saitoh
Masahiro
M
Nishimura
Riko
R
Yoneda
Toshiyuki
T
Kou
Ikuyo
I
Furuichi
Tatsuya
T
Ikegawa
Shiro
S
Ikawa
Masahito
M
Okabe
Masaru
M
Wanaka
Akio
A
Imaizumi
Kazunori
K
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C119923:Creb3l1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger