Endoplasmic reticulum (ER) stress transducers transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. BBF2 human homolog on chromosome 7 (BBF2H7) and old astrocyte specifically induced substance (OASIS), ER-resident transmembrane proteins, have recently been identified as novel ER stress transducers that have roles in chondrogenesis and osteogenesis, respectively. However, the molecular mechanisms that regulate the activation of BBF2H7 and OASIS under ER stress conditions remain unresolved. Here, we showed that BBF2H7 and OASIS are notably unstable proteins that are easily degraded via the ubiquitin-proteasome pathway under normal conditions. ER stress conditions enhanced the stability of BBF2H7 and OASIS, and promoted transcription of their target genes. HMG-CoA reductase degradation 1 (HRD1), an ER-resident E3 ubiquitin ligase, ubiquitinated BBF2H7 and OASIS under normal conditions, whereas ER stress conditions dissociated the interaction between HRD1 and BBF2H7 or OASIS. The stabilization of OASIS in Hrd1−/− cells enhanced the expression of collagen fibers during osteoblast differentiation, whereas a knockdown of OASIS in Hrd1−/− cells suppressed the production of collagen fibers. These findings suggest that ER stress stabilizes OASIS family members and this is a novel molecular mechanism for the activation of ER stress transducers.
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activating transcription factor 6
BBF2 human homologue on chromosome 7
immunoglobulin heavy chain-binding protein
bone morphogenetic protein 2
basic leucine zipper
type I collagen
coat protein complex II
cyclic AMP-response element-binding protein
cyclic AMP-response element-binding protein H
human influenza hemagglutinin
HMG-CoA reductase degradation 1
inositol requiring 1
mouse embryonic fibroblast
NF-E2-related factor 2
old astrocyte specifically induced substance
PKR-like endoplasmic reticulum kinase
regulated intramembrane proteolysis
SREBP-cleavage activating protein
sterol regulatory element-binding proteins
unfolded protein response
Wolfram syndrome 1
X-box binding protein 1
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We thank Dr. Toshihiro Nakajima (Tokyo Medical University) for kindly providing MEF(Hrd1+/+) and MEF(Hrd1−/−) cells and anti-HRD1 antibody, Dr. Lee-Yuan Liu-Chen (Temple University School of Medicine) for kindly providing the ubiquitin expression plasmids and S Nakagawa for technical support. This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#22020030, #22800049), the Takeda Science Foundation and the Pharmacological Research Foundation Tokyo.
S Kondo, SH and KI designed the experiments. S Kondo, SH, AS, S Kanemoto, NK, RA, SI, HI, MO and HM performed the experiments. S Kondo and KI wrote the manuscript. MK, YN and FU provided substantial input into the writing of the manuscript.
The authors declare no conflict of interest.
Edited by M Piacentini
Supplementary Information accompanies the paper on Cell Death and Differentiation website
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Kondo, S., Hino, S., Saito, A. et al. Activation of OASIS family, ER stress transducers, is dependent on its stabilization. Cell Death Differ 19, 1939–1949 (2012) doi:10.1038/cdd.2012.77
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