Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis

Atsushi Saito, Shin Ichiro Hino, Tomohiko Murakami, Soshi Kanemoto, Shinichi Kondo, Masahiro Saitoh, Riko Nishimura, Toshiyuki Yoneda, Tatsuya Furuichi, Shiro Ikegawa, Masahito Ikawa, Masaru Okabe, Kazunori Imaizumi

Research output: Contribution to journalArticlepeer-review

137 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1197-1204
Number of pages8
JournalNature cell biology
Volume11
Issue number10
DOIs
Publication statusPublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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