Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson’s disease models

Abstract

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: HACE1 knockdown in BV2 cells exacerbated neuroinflammation.
Fig. 2: HACE1 regulated neuroinflammation through the Rac1-NADPH oxidase pathway.
Fig. 3: HACE1 promoted the ubiquitination and degradation of Rac1- GTP.
Fig. 4: HACE1 protected SH‐SY5Y cells from LPS‐mediated neurotoxicity.
Fig. 5: HACE1 knockdown exacerbated behavior impairments in the MPTP-induced mouse model.
Fig. 6: HACE1 is reduced in the brain of A53T transgenic mice.
Fig. 7: Schematic diagram of HACE1 role in regulating the neuroinflammatory responses of BV2 microglial cells.

References

  1. 1.

    Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet. 2004;363:1783–93.

    CAS  Article  Google Scholar 

  2. 2.

    Ha D, Stone DK, Mosley RL, Gendelman HE. Immunization strategies for Parkinson’s disease. Parkinsonism Relat D. 2012;18:S218–S221.

    Article  Google Scholar 

  3. 3.

    Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8:382–97.

    CAS  Article  Google Scholar 

  4. 4.

    Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F. Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience. 1993;52:1–6.

    CAS  Article  Google Scholar 

  5. 5.

    Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol. 2005;57:168–75.

    CAS  Article  Google Scholar 

  6. 6.

    Linnerbauer M, Wheeler MA, Quintana FJ. Astrocyte crosstalk in CNS inflammation. Neuron. 2020;108:608–22.

    CAS  Article  Google Scholar 

  7. 7.

    Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: symphony of glial cells. Glia. 2019;67:1017–35.

    Article  Google Scholar 

  8. 8.

    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol. 2003;106:518–26.

    CAS  Article  Google Scholar 

  9. 9.

    Cetinbas N, Daugaard M, Mullen AR, Hajee S, Rotblat B, Lopez A, et al. Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction. Oncogene. 2015;34:4005–10.

    CAS  Article  Google Scholar 

  10. 10.

    Daugaard M, Nitsch R, Razaghi B, McDonald L, Jarrar A, Torrino S, et al. Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes. Nat Commun. 2013;4:2180.

    Article  Google Scholar 

  11. 11.

    Razaghi B, Steele SL, Prykhozhij SV, Stoyek MR, Hill JA, Cooper MD, et al. Hace1 influences zebrafish cardiac development via ROS-dependent mechanisms. Dev Dyn. 2018;247:289–303.

    CAS  Article  Google Scholar 

  12. 12.

    Chiurchiù V, Maccarrone M. Chronic inflammatory disorders and their redox control: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;15:2605–41.

    Article  Google Scholar 

  13. 13.

    Lee IT, Yang CM. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem Pharmacol. 2012;84:581–90.

    CAS  Article  Google Scholar 

  14. 14.

    Yan ZQ, Gibson SA, Buckley JA, Qin HW, Benveniste EN. Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clin Immunol. 2018;189:4–13.

    CAS  Article  Google Scholar 

  15. 15.

    Qin HW, Buckley JA, Li XR, Liu YD, Fox TH, Meares GP, et al. Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J Neurosci. 2016;36:5144–59.

    CAS  Article  Google Scholar 

  16. 16.

    Yauger YJ, Bermudez S, Moritz KE, Glaser E, Stoica B, Byrnes KR. Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro. J Neuroinflammation. 2019;16:41.

    Article  Google Scholar 

  17. 17.

    Qin LY, Liu YX, Wang TG, Wei SJ, Block ML, Wilson B, et al. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2004;279:1415–21.

    CAS  Article  Google Scholar 

  18. 18.

    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.

    CAS  Article  Google Scholar 

  19. 19.

    Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.

    CAS  Article  Google Scholar 

  20. 20.

    Goka ET, Lippman ME. Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression. Oncogene. 2015;34:5395–405.

    CAS  Article  Google Scholar 

  21. 21.

    Mettouchi A, Lemichez E. Ubiquitylation of active Rac1 by the E3 ubiquitin-ligase HACE1. Small GTPases. 2012;3:102–6.

    Article  Google Scholar 

  22. 22.

    Hurley LL, Tizabi Y. Neuroinflammation, neurodegeneration, and depression. Neurotox Res. 2013;23:131–44.

    CAS  Article  Google Scholar 

  23. 23.

    Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci. 2017;11:216.

    Article  Google Scholar 

  24. 24.

    Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35:601–12.

    CAS  Article  Google Scholar 

  25. 25.

    Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep. 2017;17:25.

    Article  Google Scholar 

  26. 26.

    Cetinbas N, Daugaard M, Mullen AR, Hajee S, Rotblat B, Lopez A, et al. Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction. Oncogene. 2015;34:4005–10.

    CAS  Article  Google Scholar 

  27. 27.

    Kumar B, Roy A, Asha K, Walia NS, Ansari MA, Chandran B. HACE1, an E3 ubiquitin protein ligase, mitigates Kaposi’s Sarcoma-associated herpesvirus infection-induced oxidative stress by promoting Nrf2 activity. J Virol. 2019;93:e01812–01818.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Milton VJ, Sweeney ST. Oxidative stress in synapse development and function. Dev Neurobiol. 2012;72:100–10.

    CAS  Article  Google Scholar 

  29. 29.

    Bischoff LJM, Kuijper IA, Schimming JP, Wolters L, Braak BT, Langenberg JP, et al. A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure. Arch Toxicol. 2019;93:435–51.

    CAS  Article  Google Scholar 

  30. 30.

    Lam GY, Huang J, Brumell JH. The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol. 2010;32:415–30.

    CAS  Article  Google Scholar 

  31. 31.

    Fernandez-Marcos PJ, Nóbrega-Pereira S. NADPH: new oxygen for the ROS theory of aging. Oncotarget. 2016;7:50814–5.

    Article  Google Scholar 

  32. 32.

    Zhang LY, Chen X, Sharma P, Moon M, Sheftel AD, Dawood F, et al. HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress. Nat Commun. 2014;5:3430.

    Article  Google Scholar 

  33. 33.

    Acosta MI, Urbach S, Doye A, Ng YW, Boudeau J, Mettouchi A, et al. Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination. Sci Rep. 2018;8:1410.

    Article  Google Scholar 

  34. 34.

    Rathinam R, Berrier A, Alahari SK. Role of Rho GTPases and their regulators in cancer progression. Front Biosci. 2011;16:2561–71.

    CAS  Article  Google Scholar 

  35. 35.

    Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 2016;1:1003.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Tansey MG, Goldberg MS. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis. 2010;37:510–8.

    CAS  Article  Google Scholar 

  37. 37.

    Lawrimore CJ, Coleman LG, Zou J, Crews FT. Ethanol induction of innate immune signals across BV2 microglia and SH-SY5Y neuroblastoma involves induction of IL-4 and IL-13. Brain Sci. 2019;9:228.

    CAS  Article  Google Scholar 

  38. 38.

    Park J, Lim CS, Seo H, Park CA, Zhuo M, Kaang BK, et al. Pain perception in acute model mice of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mol Pain. 2015;11:28.

    Article  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2016-I2M-3-011), Chinese Academy of Medical Sciences Fundamental Research Funds for the Central Universities (No. 2018RC350002), National Natural Science Foundation of China (No. 81630097, 81773718, 21772235).

Author information

Affiliations

Authors

Contributions

CXZ and DZ designed the study and drafted the manuscript. CXZ, LW, HYY, JMS carried out behavioral tests, immunohistochemistry and Western blot assay. HL, ZHZ, CJ, FYY and FYL participated in the Western blot assay. XQB revised the manuscript.

Corresponding author

Correspondence to Dan Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zang, Cx., Wang, L., Yang, Hy. et al. HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson’s disease models. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00778-2

Download citation

Keywords

  • HACE1
  • Rac1 activity
  • neuroinflammation
  • LPS
  • BV2 microglial cells
  • MPTP-induced acute PD mouse model
  • α-synuclein transgenic mice
  • Parkinson’s disease

Search

Quick links