title: Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis.
abstract: Many tissues have a specific signal transduction system for endoplasmic reticulum (ER) dysfunction; however, the mechanisms underlying the ER stress response in cartilage remain unclear. BBF2H7 (BBF2 human homologue on chromosome 7), an ER-resident basic leucine zipper transcription factor, is activated in response to ER stress and is highly expressed in chondrocytes. In this study, we generated Bbf2h7(-/-) mice to assess the in vivo function of BBF2H7. The mice showed severe chondrodysplasia and died by suffocation shortly after birth because of an immature chest cavity. The cartilage showed a lack of typical columnar structure in the proliferating zone and a decrease in the size of the hypertrophic zone, resulting in a significant reduction of extracellular matrix proteins. Interestingly, proliferating chondrocytes showed abnormally expanded ER, containing aggregated type II collagen (Col2) and cartilage oligomeric matrix protein (COMP). We identified Sec23a, which encodes a coat protein complex II component responsible for protein transport from the ER to the Golgi, as a target of BBF2H7, which directly bound to a CRE-like sequence in the promoter region of Sec23a to activate its transcription. When Sec23a was introduced to Bbf2h7(-/-) chondrocytes, the impaired transport and secretion of cartilage matrix proteins was totally restored, indicating that by activating protein secretion the BBF2H7-Sec23a pathway has a crucial role in chondrogenesis. Our findings provide a new link by which ER stress is converted to signalling for the activation of ER-to-Golgi trafficking.
authors.affiliation: Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Hino
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Murakami
authors.forename: Soshi
authors.initials: S
authors.lastname: Kanemoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kondo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Saitoh
authors.forename: Riko
authors.initials: R
authors.lastname: Nishimura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D064236:Cartilage Oligomeric Matrix Protein; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology / Q000648:ultrastructure; D020219:Chondrogenesis; D024043:Collagen Type II / Q000378:metabolism; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D064235:Matrilin Proteins; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D012272:Ribs / Q000166:cytology; D033921:Vesicular Transport Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; C544811:Creb3l2 protein, mouse; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; C079038:Sec23a protein, mouse; C577553:TSP5 protein, human; D033921:Vesicular Transport Proteins