Activation of OASIS family, ER stress transducers, is dependent on its stabilization

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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.

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androgen-induced bZIP


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






endoplasmic reticulum


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


site-1 protease


site-2 protease


SREBP-cleavage activating protein


sterol regulatory element-binding proteins


unfolded protein response


Wolfram syndrome 1


X-box binding protein 1


  1. 1

    Ron D, Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–529.

  2. 2

    Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002; 415: 92–96.

  3. 3

    Harding HP, Zhang Y, Ron D . Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397: 271–274.

  4. 4

    Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 2000; 20: 6755–6767.

  5. 5

    Shen J, Chen X, Hendershot L, Prywes RER . stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 2002; 3: 99–111.

  6. 6

    Kondo S, Saito A, Asada R, Kanemoto S, Imaizumi K . Physiological unfolded protein response regulated by CREB/ATF family members, transmembrane bZIP transcription factors. IUBMB Life 2011; 63: 233–239.

  7. 7

    Asada R, Kanemoto S, Kondo S, Saito A, Imaizumi K . The signaling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellullar physiology. J Biochem 2011; 149: 507–518.

  8. 8

    DenBoer LM, Hardy-Smith PW, Hogan MR, Cockram GP, Audas TE, Lu R . Luman is capable of binding and activating transcription from the unfolded protein response element. Biochem Biophys Res Commun 2005; 331: 113–119.

  9. 9

    Kondo S, Murakami T, Tatsumi K, Ogata M, Kanemoto S, Otori K et al. OASIS, a CREB/ATF-family member, modulates UPR signaling in astrocytes. Nat Cell Biol 2005; 7: 186–194.

  10. 10

    Kondo S, Saito A, Hino S-I, Murakami T, Ogata M, Kanemoto S et al. BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer. Mol Cell Biol 2007; 27: 1716–1729.

  11. 11

    Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 2006; 124: 587–599.

  12. 12

    Nagamori I, Yabuta N, Fujii T, Tanaka H, Yomogida K, Nishimune Y et al. Tisp40, a spermatid specific bZip transcription factor, functions by binding to the unfolded protein response element via the Rip pathway. Genes Cells 2005; 10: 575–594.

  13. 13

    Stirling J, O’Hare P . CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Mol Biol Cell 2006; 17: 413–426.

  14. 14

    Murakami T, Saito A, Hino S-I, Kondo S, Kanemoto S, Chihara K et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol 2009; 11: 1205–1211.

  15. 15

    Saito A, Hino S-I, Murakami T, Kanemoto S, Kondo S, Saitoh M et al. Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nat Cell Biol 2009; 11: 1197–1204.

  16. 16

    Cao G, Ni X, Jiang M, Ma Y, Cheng H, Guo L et al. Molecular cloning and characterization of a novel human cAMP response element-binding (CREB) gene (CREB4). J Hum Genet 2002; 47: 373–376.

  17. 17

    Brown MS, Ye J, Rawson RB, Goldstein JL . Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000; 100: 391–398.

  18. 18

    Bailey D, O’Hare P . Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid Redox Signal 2007; 9: 2305–2321.

  19. 19

    Murakami T, Kondo S, Ogata M, Kanemoto S, Saito A, Wanaka A et al. Cleavage of the membrane-bound transcription factor OASIS in response to endoplasmic reticulum stress. J Neurochem 2006; 96: 1090–1100.

  20. 20

    Chen C, Sun X, Ran Q, Wilkinson KD, Murphy TJ, Simons JW et al. Ubiquitin-proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells. Oncogene 2005; 24: 3319–3327.

  21. 21

    Pickart CM . Back to the future with ubiquitin. Cell 116: 181–190.

  22. 22

    Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest 2010; 120: 744–755.

  23. 23

    Tohmonda T, Miyauchi Y, Ghosh R, Yoda M, Uchikawa S, Takito J et al. The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep 2011; 12: 451–457.

  24. 24

    Amano T, Yamasaki S, Yagishita N, Tsuchimochi K, Shin H, Kawahara K et al. Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev 2003; 17: 2436–2449.

  25. 25

    Christianson JC, Shaler TA, Tyler RE, Kopito RR . OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat Cell Biol 2008; 10: 272–282.

  26. 26

    Omura T, Kaneko M, Okuma Y, Orba Y, Nagashima K, Takahashi R et al. A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. J Neurochem 2006; 99: 1456–1469.

  27. 27

    Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y . Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci 2010; 30: 3924–3932.

  28. 28

    Taguchi K, Motohashi H, Yamamoto M . Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011; 16: 123–140.

  29. 29

    DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ . Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 1999; 99: 703–712.

  30. 30

    Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110: 489–500.

  31. 31

    Brown AJ, Sun L, Feramisco JD, Brown MS, Goldstein JL . Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 2002; 10: 237–245.

  32. 32

    Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL . Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell 2004; 15: 259–268.

  33. 33

    Li JG, Haines DS, Liu-Chen LY . Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation. Mol Pharmacol 2008; 73: 1319–1330.

  34. 34

    Omura T, Kaneko M, Onoguchi M, Koizumi S, Itami M, Ueyama M et al. Novel functions of ubiquitin ligase HRD1 with transmembrane and proline-rich domains. J Pharmacol Sci 2008; 106: 512–519.

  35. 35

    Yamasaki S, Yagishita N, Sasaki T, Nakazawa M, Kato Y, Yamadera T et al. Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'. EMBO J 2007; 26: 113–122.

  36. 36

    Domenicucci C, Goldberg HA, Hofmann T, Isenman D, Wasi S, Sodek J . Characterization of porcine osteonectin extracted from foetal calvariae. Biochem J 1988; 253: 139–151.

  37. 37

    Erickson AH, Blobel G . Early events in the biosynthesis of the lysosomal enzyme Cathepsin D. J Biol Chem 1979; 254: 11771–11774.

  38. 38

    Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M . Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 1997; 272: 18842–18848.

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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.

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Correspondence to S Kondo or K Imaizumi.

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The authors declare no conflict of interest.

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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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  • ER stress response
  • BBF2H7
  • degradation
  • HRD1

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