Skip to main content

Advertisement

SpringerLink
Log in

HSP70 attenuates neuronal necroptosis through the HSP90α-RIPK3 pathway following neuronal trauma

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Necroptosis, a newly defined regulatable necrosis with membrane disruption, has been demonstrated to participate in trauma brain injury (TBI) related neuronal cell death. Heat shock protein 70 (HSP70) is a stress protein with neuroprotective activity, but the potential protective mechanisms are not fully understood.

Methods and results

Here, we investigated the effects of HSP70 regulators in a cellular TBI model induced by traumatic neuronal injury (TNI) and glutamate treatment. We found that necroptosis occurred in cortical neurons after TNI and glutamate treatment. Neuronal trauma markedly upregulated HSP70 protein expression within 24 h. The results of immunostaining and lactate dehydrogenase release assay showed that necroptosis following neuronal trauma was inhibited by HSP70 activator TRC051384 (TRC), but promoted by the HSP70 inhibitor 2-phenylethyenesulfonamide (PES). In congruent, the expression and phosphorylation of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) were differently regulated by HSP70. Furthermore, the expression of HSP90α induced by neuronal trauma was further promoted by PES but decreased by TRC. The data obtained from western blot showed that the phosphorylation of RIPK3 and MLKL induced by HSP70 inhibition were reduced by RIPK3 inhibitor GSK-872 and HSP90α inhibitor geldanamycin (GA). Similarly, inhibition of HSP90α with GA could partially prevented the increased necroptosis induced by PES.

Conclusions

Taken together, HSP70 activation exerted protective effects against neuronal trauma via inhibition of necroptosis. Mechanistically, the HSP90α-mediated activation of RIPK3 and MLKL is involved in these effects.

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

Similar content being viewed by others

Data availability

Dara will be available on reasonable request.

References

  1. Wiles MD (2022) Management of traumatic brain injury: a narrative review of current evidence. Anaesthesia 77(Suppl 1):102–112

    Article  PubMed  Google Scholar 

  2. Hu X et al (2022) Role of necroptosis in traumatic brain and spinal cord injuries. J Adv Res 40:125–134

    Article  CAS  PubMed  Google Scholar 

  3. Sharp FR, Zhan X, Liu DZ (2013) Heat shock proteins in the brain: role of Hsp70, hsp 27, and HO-1 (Hsp32) and their therapeutic potential. Transl Stroke Res 4(6):685–692

    Article  CAS  PubMed  Google Scholar 

  4. Kim JY et al (2020) Heat shock protein 70 (HSP70) induction chaperonotherapy for neuroprotection after brain Injury. Cells 9(9):2020

    Article  CAS  PubMed Central  Google Scholar 

  5. Sun Y et al (2006) The carboxyl-terminal domain of inducible Hsp70 protects from ischemic injury in vivo and in vitro. J Cereb Blood Flow Metab 26(7):937–950

    Article  CAS  PubMed  Google Scholar 

  6. Doeppner TR et al (2009) TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 29(6):1187–1196

    Article  CAS  PubMed  Google Scholar 

  7. Kim JY et al (2013) The 70 kDa heat shock protein protects against experimental traumatic brain injury. Neurobiol Dis 58:289–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gu Y et al (2016) Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury. Exp Ther Med 12(6):3767–3772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen T et al (2012) Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons. Free Radic Biol Med 52(1):208–217

    Article  CAS  PubMed  Google Scholar 

  10. Chen T et al (2022) Edonerpic maleate regulates glutamate receptors through CRMP2- and Arc-mediated mechanisms in response to brain trauma. Cell Death Discov 8(1):95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. da Rocha AB et al (2005) Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males. J Neurotrauma 22(9):966–977

    Article  PubMed  Google Scholar 

  12. Zurek J, Fedora M (2012) The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury. Acta Neurochir (Wien) 154(1):93–103

    Article  PubMed  Google Scholar 

  13. Chio CC et al (2017) Exercise attenuates neurological deficits by stimulating a critical HSP70/NF-kappaB/IL-6/synapsin I axis in traumatic brain injury rats. J Neuroinflamm 14(1):90

    Article  Google Scholar 

  14. Tandean S et al (2019) Protective Effects of Propolis Extract in a rat model of traumatic brain Injury via Hsp70 induction. Open Access Maced J Med Sci 7(17):2763–2766

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang MH et al (2018) Neuroprotective effects of dexmedetomidine on traumatic brain injury: involvement of neuronal apoptosis and HSP70 expression. Mol Med Rep 17(6):8079–8086

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu X et al (2016) Heat shock protein 70 inhibits cardiomyocyte necroptosis through repressing autophagy in myocardial ischemia/reperfusion injury. In Vitro Cell Dev Biol Anim 52(6):690–698

    Article  CAS  PubMed  Google Scholar 

  17. Srinivasan SR et al (2018) Heat shock protein 70 (Hsp70) suppresses RIP1-Dependent apoptotic and necroptotic cascades. Mol Cancer Res 16(1):58–68

    Article  CAS  PubMed  Google Scholar 

  18. Yashin DV et al (2016) The Tag7-Hsp70 cytotoxic complex induces tumor cell necroptosis via permeabilisation of lysosomes and mitochondria. Biochimie 123:32–36

    Article  CAS  PubMed  Google Scholar 

  19. Johnston AN, Wang Z (2020) HSP70 promotes MLKL polymerization and necroptosis. Mol Cell Oncol 7(5):1791561

    Article  PubMed  PubMed Central  Google Scholar 

  20. Johnston AN et al (2020) Necroptosis-blocking compound NBC1 targets heat shock protein 70 to inhibit MLKL polymerization and necroptosis. Proc Natl Acad Sci U S A 117(12):6521–6530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Degterev A et al (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1(2):112–119

    Article  CAS  PubMed  Google Scholar 

  22. Li X et al (2021) Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice. Cell Death Discov 7(1):338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang L et al (2019) TRADD mediates RIPK1-independent necroptosis induced by tumor necrosis factor. Front Cell Dev Biol 7:393

    Article  PubMed  Google Scholar 

  24. Su L et al (2014) A plug release mechanism for membrane permeation by MLKL. Structure 22(10):1489–1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Seo J et al (2016) CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3. Nat Cell Biol 18(3):291–302

    Article  CAS  PubMed  Google Scholar 

  26. Yong Y et al (2021) ERK1/2 mitogen-activated protein kinase mediates downregulation of intestinal tight junction proteins in heat stress-induced IBD model in pig. J Therm Biol 101:103103

    Article  CAS  PubMed  Google Scholar 

  27. Taipale M et al (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150(5):987–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou X et al (2019) Heat shock protein 90alpha-dependent B-cell-2-associated transcription factor 1 promotes hepatocellular carcinoma proliferation by regulating MYC proto-oncogene c-MYC mRNA stability. Hepatology 69(4):1564–1581

    Article  CAS  PubMed  Google Scholar 

  29. Li D et al (2015) A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis. Proc Natl Acad Sci USA 112(16):5017–5022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lewis J et al (2000) Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappab activation. J Biol Chem 275(14):10519–10526

    Article  CAS  PubMed  Google Scholar 

  31. Wang Z et al (2018) Inhibition of HSP90alpha protects cultured neurons from oxygen-glucose deprivation induced necroptosis by decreasing RIP3 expression. J Cell Physiol 233(6):4864–4884

    Article  CAS  PubMed  Google Scholar 

  32. Liao LS et al (2021) The role of HSP90alpha in Methamphetamine/Hyperthermia-Induced necroptosis in rat striatal neurons. Front Pharmacol 12:716394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by the National Natural Science Foundation of China (No. 82072168 and No. 81871589), the Natural Science Foundation of Jiangsu Province (No. BK20211044), the Major Scientific Research Project of Wuxi Health Commission (No. Z202001), the top talent support program for young and middle-aged people of Wuxi health committee (BJ2020118), the Translational Medicine Research Major Project of Wuxi Health Commission (No. ZH201901), the China Postdoctoral Science Foundation funded project (No. 2019M651803), and the Logistics Scientific Research Project of PLA (No. CLB20J027).

Author information

Author notes

  1. Tao Chen, Yun-Na Tao and Yan Wu contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Wuxi Taihu Hospital, Wuxi Clinical College of Anhui Medical University, Wuxi, 214044, Jiangsu, China

    Tao Chen, Yun-Na Tao, Yan Wu, Xu Ren, Yun-Fei Li & Yu-Hai Wang

Authors
  1. Tao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Na Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xu Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun-Fei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Hai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Hai Wang.

Ethics declarations

Conflict of interest

Tao Chen declares that he has no conflict of interest. Yun-Na Tao declares that she has no conflict of interest. Yan Wu declares that she has no conflict of interest. Xu Ren declares that he has no conflict of interest. Yun-Fei Li declares that he has no conflict of interest. Yu-Hai Wang declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Tao, YN., Wu, Y. et al. HSP70 attenuates neuronal necroptosis through the HSP90α-RIPK3 pathway following neuronal trauma. Mol Biol Rep 50, 7237–7244 (2023). https://doi.org/10.1007/s11033-023-08619-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-023-08619-7

Keywords

Search

Navigation