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PMID:19767744

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Citation

Saito, A, Hino, S, Murakami, T, Kanemoto, S, Kondo, S, Saitoh, M, Nishimura, R, Yoneda, T, Furuichi, T, Ikegawa, S, Ikawa, M, Okabe, M and Imaizumi, K (2009) Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nat. Cell Biol. 11:1197-204

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.

Links

PubMed Online version:10.1038/ncb1962

Keywords

Animals; Basic-Leucine Zipper Transcription Factors/metabolism; Cartilage, Articular/cytology; Cells, Cultured; Chondrocytes/physiology; Chondrocytes/ultrastructure; Chondrogenesis; Collagen Type II/metabolism; Embryo, Mammalian; Endoplasmic Reticulum/physiology; Endoplasmic Reticulum/ultrastructure; Extracellular Matrix Proteins/metabolism; Gene Expression Regulation, Developmental; Glycoproteins/metabolism; Golgi Apparatus/metabolism; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Knockout; Protein Transport; Ribs/cytology; Vesicular Transport Proteins/biosynthesis; Vesicular Transport Proteins/genetics; Vesicular Transport Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CR3L2

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CR3L2

enables

GO:0035497: cAMP response element binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CR3L2

involved_in

GO:0002062: chondrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CR3L2

involved_in

GO:0006888: endoplasmic reticulum to Golgi vesicle-mediated transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CR3L2

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CR3L2

involved_in

GO:0051216: cartilage development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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