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Connecting the Dots in the Neuroglobin-Protein Interaction Network of an Unstressed and Ferroptotic Cell Death Neuroblastoma Model

1
Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium
2
Centre for Proteomics (CFP), University of Antwerp, 2610 Wilrijk, Belgium
3
Department of Ophthalmology, Visual Optics and Visual Rehabilitation, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Wilrijk, Belgium
4
Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
5
Laboratory of Experimental Hematology (LEH), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Wilrijk, Belgium
*
Author to whom correspondence should be addressed.
Cells 2019, 8(8), 873; https://doi.org/10.3390/cells8080873
Received: 11 July 2019 / Revised: 3 August 2019 / Accepted: 7 August 2019 / Published: 11 August 2019
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Abstract

Neuroglobin is a heme protein of which increased levels provide neuroprotection against amyloid proteinopathy and hemorrhagic damage. These cellular stressors involve the promotion of ferroptosis—an iron-dependent, lipid peroxide-accreting form of cell death. Hence, we questioned whether neuroglobin could oppose ferroptosis initiation. We detected human neuroglobin (hNgb)-EGFP-expressing SH-SY5Y cells to be significantly more resistant to ferroptosis induction, identifying 0.68-fold less cell death. To elucidate the underlying pathways, this study investigated hNgb-protein interactions with a Co-IP-MS/MS approach both under a physiological and a ferroptotic condition. hNgb binds to proteins of the cellular iron metabolism (e.g., RPL15 and PCBP3) in an unstressed condition and shows an elevated binding ratio towards cell death-linked proteins, such as HNRNPA3, FAM120A, and ABRAXAS2, under ferroptotic stress. Our data also reveal a constitutive interaction between hNgb and the longevity-associated heterodimer XRCC5/XRCC6. Disentangling the involvement of hNgb and its binding partners in cellular processes, using Ingenuity Pathway Analysis, resulted in the integration of hNgb in the ubiquitination pathway, mTOR signaling, 14-3-3-mediated signaling, and the glycolysis cascade. We also detected a previously unknown strong link with motor neuropathies. Hence, this study contributes to the elucidation of neuroglobin’s involvement in cellular mechanisms that provide neuroprotection and the upkeep of homeostasis. View Full-Text
Keywords: neuroglobin; ferroptosis; protein-interaction network; neuroprotection neuroglobin; ferroptosis; protein-interaction network; neuroprotection
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Van Acker, Z.P.; Van Raemdonck, G.A.; Logie, E.; Van Acker, S.I.; Baggerman, G.; Vanden Berghe, W.; Ponsaerts, P.; Dewilde, S. Connecting the Dots in the Neuroglobin-Protein Interaction Network of an Unstressed and Ferroptotic Cell Death Neuroblastoma Model. Cells 2019, 8, 873.

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