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

Nature Cell Biology volume 11, pages 1197–1204 (2009)Cite this article

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 stress1 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 Golgi2,3, 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.

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Figure 1: Bbf2h7−/− mice show severe chondrodysplasia.
Figure 2: Col2 and cartilage oligomeric matrix protein (COMP) are accumulated in the ER lumen in Bbf2h7-deficient mice.
Figure 3: Expression of chondrocyte differentiation markers and ER stress-related genes in cultured cells.
Figure 4: Sec23a is a target of BBF2H7.
Figure 5: The introduction of Sec23a in Bbf2h7−/− cells improves secretion of ECM proteins.

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Acknowledgements

We thank M. Tohyama and S. Shiosaka for helpful discussions and critical reading of the manuscript, and K. Ogawa, A. Ikeda, I. Tsuchimochi, T. Kawanami, A. Kawai and Y. Koreeda for technical support. This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#19659082, #20059028, #19790238 and #20-3757) and The Novartis Foundation (Japan) for the Promotion of Science.

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Author notes

  1. Atsushi Saito and Shin-ichiro Hino: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, 889-1692, Miyazaki, Japan

    Atsushi Saito, Shin-ichiro Hino, Tomohiko Murakami, Soshi Kanemoto, Shinichi Kondo & Kazunori Imaizumi

  2. The Department of Molecular and Cellular Biochemistry, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Masahiro Saitoh, Riko Nishimura & Toshiyuki Yoneda

  3. Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Tatsuya Furuichi & Shiro Ikegawa

  4. Genome Information Research Center and Graduate School of Pharmaceutical Sciences, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Masahito Ikawa & Masaru Okabe

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  1. Atsushi Saito
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Contributions

A.S. and K.I. designed experiments. A.S., S.H., T.M., S.Ka and S.Ko performed experiments. M.S., R.N., T.Y., T.F. and S.I. guided cartilage experiments. S.H., M.I. and M.O. generated Bbf2h7−/− mice. R.N., T.Y., S.I. and M.O. helped write the manuscript. A.S. and K.I. wrote the manuscript. K.I. supervised the project.

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Correspondence to Kazunori Imaizumi.

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The authors declare no competing financial interests.

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Saito, A., Hino, Si., Murakami, T. et al. Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nat Cell Biol 11, 1197–1204 (2009). https://doi.org/10.1038/ncb1962

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