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

A Saito, S Hino, T Murakami, S Kanemoto, S Kondo… - Nature cell …, 2009 - nature.com
A Saito, S Hino, T Murakami, S Kanemoto, S Kondo, M Saitoh, R Nishimura, T Yoneda…
Nature cell biology, 2009nature.com
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 …
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.
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