Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 20, Pages 13810-13820Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.543322
Keywords
Cartilage; Cell Biology; Chondrogenesis; Protein Secretion; Transcription Factors; BBF2H7; ER Stress Transducer; Sox9
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Funding
- Japan Society for the Promotion of Science KAKENHI [25251014, 25650069, 24689058, 24659678]
- Takeda Science Foundation
- SEI Group CSR Foundation
- INAMORI FOUNDATION
- Uehara Memorial Foundation
- Princess Takamatsu Cancer Research Fund
- Cell Science Research Foundation
- Grants-in-Aid for Scientific Research [24659678, 24689058, 25251014, 13J00677, 25650069] Funding Source: KAKEN
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Background: BBF2H7 promotes cartilage matrix protein secretion through activation of Sec23a expression during chondrogenesis. Results: Sox9 induces BBF2H7 expression, followed by accelerating secretion of cartilage matrix proteins in chondrocytes. Conclusion: Sox9 simultaneously induces Bbf2h7 and Col2, followed by promoting secretion of Col2 through activation of BBF2H7-Sec23a signaling. Significance: This might be the first to define mechanisms for cartilage matrix protein secretion regulated by Sox9. The endoplasmic reticulum (ER) stress transducer, box B-binding factor 2 human homolog on chromosome 7 (BBF2H7), is a basic leucine zipper (bZIP) transmembrane transcription factor. This molecule is activated in response to ER stress during chondrogenesis. The activated BBF2H7 accelerates cartilage matrix protein secretion through the up-regulation of Sec23a, which is responsible for protein transport from the ER to the Golgi apparatus and is a target of BBF2H7. In the present study, we elucidated the mechanisms of the transcriptional activation of Bbf2h7 in chondrocytes. The transcription of Bbf2h7 is regulated by Sex determining region Y-related high-mobility group box 9 (Sox9), a critical factor for chondrocyte differentiation that facilitates the expression of one of the major cartilage matrix proteins Type II collagen (Col2), through binding to the Sox DNA-binding motif in the Bbf2h7 promoter. BBF2H7 is activated as a transcription factor in response to physiological ER stress caused by abundant synthesis of cartilage matrix proteins, and consequently regulates the secretion of cartilage matrix proteins. Taken together, our findings demonstrate novel regulatory mechanisms of Sox9 for controlling the secretion of cartilage matrix proteins through the activation of BBF2H7-Sec23a signaling during chondrogenesis.
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