Journal
CELL DEATH AND DIFFERENTIATION
Volume 19, Issue 12, Pages 1939-1949Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2012.77
Keywords
ER stress response; BBF2H7; OASIS; degradation; HRD1
Categories
Funding
- Japan Society for the Promotion of Science KAKENHI [22020030, 22800049]
- Takeda Science Foundation
- Pharmacological Research Foundation Tokyo
- Grants-in-Aid for Scientific Research [22800049, 23790095, 22020030] Funding Source: KAKEN
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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. Cell Death and Differentiation (2012) 19, 1939-949; doi:10.1038/cdd.2012.77; published online 15 June 2012
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