Activation of OASIS family, ER stress transducers, is dependent on its stabilization.
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.
Department of Biochemistry, Institute of Biomedical and Health Sciences, University of Hiroshima, Hiroshima 734-8553, Japan. shkondo@hiroshima-u.ac.jp
S
S
Kondo
S-I
SI
Hino
A
A
Saito
S
S
Kanemoto
N
N
Kawasaki
R
R
Asada
S
S
Izumi
H
H
Iwamoto
M
M
Oki
H
H
Miyagi
M
M
Kaneko
Y
Y
Nomura
F
F
Urano
K
K
Imaizumi
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D050976:Basic-Leucine Zipper Transcription Factors; C485618:CREB3L1 protein, human; C518609:CREB3L2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D025801:Ubiquitin; D003094:Collagen; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex