Skip to main content
SpringerLink
Log in

OTUB1 attenuates neuronal apoptosis after intracerebral hemorrhage

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

OTUB1 is a member of deubiquitinating enzymes, which was shown as a proteasome-associated DUB to be involved in the proteins Ub-dependent degradation. Previous studies have indicated that OTUB1 was expressed in brain. But its distribution and function in the brain remain unclear. In this study, we explored the roles of OTUB1 protein in the pathophysiology of intracerebral hemorrhage (ICH). From the results of Western blot, immunohistochemistry, and immunofluorescence, we found an obvious up-regulation of OTUB1 in neurons adjacent to the hematoma after ICH. Furthermore, we also found that the increase of OTUB1 expression was accompanied by the enhanced expression of Bax and active caspase-3, and decreased expression of Bcl-2 in the pathological process of rat ICH. What’s more, our in vitro study, using OTUB1 RNA interference in PC12 cells, suggested that OTUB1 might exert its anti-apoptotic function in neuronal apoptosis. Therefore, OTUB1 may play a role in protecting the brain from secondary damage following ICH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Yang Z, Yu A, Liu Y, Shen H, Lin C, Lin L, Wang S, Yuan B (2014) Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int Immunopharmacol 22(2):522–525. doi:10.1016/j.intimp.2014.06.037

    Article  CAS  PubMed  Google Scholar 

  2. Kuramatsu JB, Huttner HB, Schwab S (2013) Advances in the management of intracerebral hemorrhage. J Neural Transm 120(Suppl 1):S35–S41. doi:10.1007/s00702-013-1040-y

    Article  PubMed  Google Scholar 

  3. Bimpis A, Papalois A, Tsakiris S, Zarros A, Kalafatakis K, Botis J, Stolakis V, Zissis KM, Liapi C (2012) Activation of acetylcholinesterase after U-74389G administration in a porcine model of intracerebral hemorrhage. Metab Brain Dis 27(2):221–225. doi:10.1007/s11011-012-9301-2

    Article  CAS  PubMed  Google Scholar 

  4. Thiex R, Tsirka SE (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus 22(5):E6

    Article  PubMed  Google Scholar 

  5. Su X, Wang H, Zhu L, Zhao J, Pan H, Ji X (2013) Ethyl pyruvate ameliorates intracerebral hemorrhage-induced brain injury through anti-cell death and anti-inflammatory mechanisms. Neuroscience 245:99–108. doi:10.1016/j.neuroscience.2013.04.032

    Article  CAS  PubMed  Google Scholar 

  6. D’Amelio M, Sheng M, Cecconi F (2012) Caspase-3 in the central nervous system: beyond apoptosis. Trends Neurosci 35(11):700–709. doi:10.1016/j.tins.2012.06.004

    Article  PubMed  Google Scholar 

  7. Dewson G (2015) Investigating Bax subcellular localization and membrane integration. Cold Spring Harbor Protoc 2015(5):467–471. doi:10.1101/pdb.prot086447

    Google Scholar 

  8. Fang CC, Yen CJ, Tsai TJ, Chen RH, Lee PH, Tomino Y (2003) Antibiotics induce apoptosis of human peritoneal mesothelial cells. Nephrology 8(3):142–149

    Article  CAS  PubMed  Google Scholar 

  9. Nan A, Zhou X, Chen L, Liu M, Zhang N, Zhang L, Luo Y, Liu Z, Dai L, Jiang Y (2016) A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis. Oncotarget 7(1):112–124. doi:10.18632/oncotarget.6590

    PubMed  Google Scholar 

  10. Crandall KM, Rost NS, Sheth KN (2011) Prognosis in intracerebral hemorrhage. Rev Neurol Dis 8(1–2):23–29

    PubMed  Google Scholar 

  11. Liu X, Jiang WN, Wang JG, Chen H (2014) Colon cancer bears overexpression of OTUB1. Pathol Res Pract 210(11):770–773. doi:10.1016/j.prp.2014.05.008

    Article  CAS  PubMed  Google Scholar 

  12. Magraoui FE, Reidick C, Meyer HE, Platta HW (2015) Autophagy-related deubiquitinating enzymes involved in health and disease. Cells 4(4):596–621. doi:10.3390/cells4040596

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5):773–786. doi:10.1016/j.cell.2005.11.007

    Article  CAS  PubMed  Google Scholar 

  14. Sowa ME, Bennett EJ, Gygi SP, Harper JW (2009) Defining the human deubiquitinating enzyme interaction landscape. Cell 138(2):389–403. doi:10.1016/j.cell.2009.04.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wilkinson KD (2009) DUBs at a glance. J Cell Sci 122(Pt 14):2325–2329. doi:10.1242/jcs.041046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O’Donnell L, Kumakubo A, Munro M, Sicheri F et al (2010) Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466(7309):941–946. doi:10.1038/nature09297

    Article  CAS  PubMed  Google Scholar 

  17. Goncharov T, Niessen K, de Almagro MC, Izrael-Tomasevic A, Fedorova AV, Varfolomeev E, Arnott D, Deshayes K, Kirkpatrick DS, Vucic D (2013) OTUB1 modulates c-IAP1 stability to regulate signalling pathways. EMBO J 32(8):1103–1114. doi:10.1038/emboj.2013.62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang Y, Hu R, Wu H, Jiang W, Sun Y, Wang Y, Song Y, Jin T, Zhang H, Mao X et al (2012) OTUB1 overexpression in mesangial cells is a novel regulator in the pathogenesis of glomerulonephritis through the decrease of DCN level. PLoS One 7(1):e29654. doi:10.1371/journal.pone.0029654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33(10):2478–2484

    Article  PubMed  Google Scholar 

  20. Ke K, Li L, Rui Y, Zheng H, Tan X, Xu W, Cao J, Xu J, Cui G, Xu G et al (2013) Increased expression of small heat shock protein alphaB-crystallin after intracerebral hemorrhage in adult rats. J Mol Neurosci 51(1):159–169. doi:10.1007/s12031-013-9970-2

    Article  CAS  PubMed  Google Scholar 

  21. Chen Z, Ruan Q, Han S, Xi L, Jiang W, Jiang H, Ostrov DA, Cai J (2014) Discovery of structure-based small molecular inhibitor of alphaB-crystallin against basal-like/triple-negative breast cancer development in vitro and in vivo. Breast Cancer Res Treat 145(1):45–59. doi:10.1007/s10549-014-2940-8

    Article  CAS  PubMed  Google Scholar 

  22. Egashira Y, Hua Y, Keep RF, Xi G (2015) Intercellular cross-talk in intracerebral hemorrhage. Brain Res 1623:97–109. doi:10.1016/j.brainres.2015.04.003

    Article  CAS  PubMed  Google Scholar 

  23. Carpenter AM, Singh IP, Gandhi CD, Prestigiacomo CJ (2016) Genetic risk factors for spontaneous intracerebral haemorrhage. Nat Rev Neurol 12(1):40–49. doi:10.1038/nrneurol.2015.226

    Article  CAS  PubMed  Google Scholar 

  24. Sun XX, Dai MS (2014) Deubiquitinating enzyme regulation of the p53 pathway: a lesson from Otub1. World J Biol Chem 5(2):75–84. doi:10.4331/wjbc.v5.i2.75

    PubMed  PubMed Central  Google Scholar 

  25. Iglesias-Gato D, Chuan YC, Jiang N, Svensson C, Bao J, Paul I, Egevad L, Kessler BM, Wikstrom P, Niu Y et al (2015) OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. Mol Cancer 14:8. doi:10.1186/s12943-014-0280-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou Y, Wu J, Fu X, Du W, Zhou L, Meng X, Yu H, Lin J, Ye W, Liu J et al (2014) OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer. Mol Cancer 13:258. doi:10.1186/1476-4598-13-258

    Article  PubMed  PubMed Central  Google Scholar 

  27. Xia Q, Liao L, Cheng D, Duong DM, Gearing M, Lah JJ, Levey AI, Peng J (2008) Proteomic identification of novel proteins associated with Lewy bodies. Front Biosci 13:3850–3856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shan TL, Tang ZL, Guo DZ, Yang SL, Mu YL, Ma YH, Guan WJ, Li K (2009) Partial molecular cloning, characterization, and analysis of the subcellular localization and expression patterns of the porcine OTUB1 gene. Mol Biol Rep 36(6):1573–1577. doi:10.1007/s11033-008-9353-x

    Article  CAS  PubMed  Google Scholar 

  29. Gong C, Hoff JT, Keep RF (2000) Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res 871(1):57–65

    Article  CAS  PubMed  Google Scholar 

  30. Li A, Li L, Sun X, Ni Y, Chen X, Guo A, Chen X (2015) Increased expression of mitochondrial inner-membrane protein Mpv17 after intracerebral hemorrhage in adult rats. Neurochem Res 40(8):1620–1630. doi:10.1007/s11064-015-1644-8

    Article  CAS  PubMed  Google Scholar 

  31. Matsushita K, Meng W, Wang X, Asahi M, Asahi K, Moskowitz MA, Lo EH (2000) Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metabol 20(2):396–404. doi:10.1097/00004647-200002000-00022

    Article  CAS  Google Scholar 

  32. Plesnila N, von Baumgarten L, Retiounskaia M, Engel D, Ardeshiri A, Zimmermann R, Hoffmann F, Landshamer S, Wagner E, Culmsee C (2007) Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-kappaB transcriptional activity. Cell Death Differ 14(8):1529–1541. doi:10.1038/sj.cdd.4402159

    Article  CAS  PubMed  Google Scholar 

  33. Cregan SP, MacLaurin JG, Craig CG, Robertson GS, Nicholson DW, Park DS, Slack RS (1999) Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J Neurosci 19(18):7860–7869

    CAS  PubMed  Google Scholar 

  34. Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99–104. doi:10.1038/sj.cdd.4400476

    Article  CAS  PubMed  Google Scholar 

  35. Huang M, Hu YY, Dong XQ, Xu QP, Yu WH, Zhang ZY (2012) The protective role of oxymatrine on neuronal cell apoptosis in the hemorrhagic rat brain. J Ethnopharmacol 143(1):228–235. doi:10.1016/j.jep.2012.06.028

    Article  CAS  PubMed  Google Scholar 

  36. Han L, Ni Y, Cao M, Zhu L, Dai A, Xu Z, Liu X, Chen R, Ning X, Ke K (2016) A new role discovered for IGTP: the protective effect of IGTP in ICH-induced neuronal apoptosis. Cell Mol Neurobiol 36(5):713–724. doi:10.1007/s10571-015-0251-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 81471188, 81371299).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

      Lili Xie, Aihong Li, Jiabing Shen, Maohong Cao, Xiaojin Ning, Debin Yuan, Yuteng Ji, Hongmei Wang & Kaifu Ke

    2. Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

      Lili Xie, Jiabing Shen, Xiaojin Ning, Debin Yuan, Yuteng Ji & Hongmei Wang

    Authors
    1. Lili Xie
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Aihong Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jiabing Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Maohong Cao
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiaojin Ning
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Debin Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yuteng Ji
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Hongmei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Kaifu Ke
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Kaifu Ke.

    Ethics declarations

    Conflict of interest

    The authors declare no conflict of interest.

    Additional information

    Lili Xie and Aihong Li contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Xie, L., Li, A., Shen, J. et al. OTUB1 attenuates neuronal apoptosis after intracerebral hemorrhage. Mol Cell Biochem 422, 171–180 (2016). https://doi.org/10.1007/s11010-016-2817-8

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11010-016-2817-8

    Keywords

    Search

    Navigation