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Nuclear factor erythroid 2 - related factor 2 and its relationship with cellular response in nickel exposure: a
Luisa Jiménez-Vidal1, Pedro Espitia-Pérez1, José Torres-Ávila2
1Facultad de Ciencias de la Salud, Grupo de Investigación Biomédica y Biología Molecular, Universidad del Sinú, Calle 38 Cra 1W, Barrio Juan XXIII, Montería, Córdoba, Colombia.
Background:
Nickel and nickel-containing compounds (NCC) are known human carcinogens. However, the precise molecular mechanisms of nickel-induced malignant transformation remain unknown. Proposed mechanisms suggest that nickel and NCC may participate in the dual activation/inactivation of enzymatic pathways involved in cell defenses against oxidative damage, where Nuclear factor-erythroid 2 related factor 2 (Nrf2) plays a central role.
Methods:
For assessing the potential role of proteins involved in the Nrf2-mediated response to nickel and NCC exposure, we designed an interactome network using the STITCH search engine version 5.0 and the STRING software 10.0. The major NCC-protein interactome (NCPI) generated was analyzed using the MCODE plugin, version 1.5.1 for the detection of interaction modules or subnetworks. Main centralities of the NCPI were determined with the CentiScape 2.2 plugin of Cytoscape 3.4.0 and main biological processes associated with each cluster were assessed using the BiNGO plugin of Cytoscape 3.4.0.
Results:
Water-soluble NiSO4 and insoluble Ni3S2 were the most connected to proteins involved in the NCPI network. Nfr2 was detected as one of the most relevant proteins in the network, participating in several multifunctional protein complexes in clusters 1, 2, 3 and 5. Ontological analysis of cluster 3 revealed several processes related to unfolded protein response (UPR) and response to endoplasmic reticulum (ER) stress.
Conclusions:
Cellular response to NCC exposure was very comparable, particularly concerning oxidative stress response, inflammation, cell cycle/proliferation, and apoptosis. In this cellular response, Nfr2 was highly centralized and participated in several multifunctional protein complexes, including several related to ER-stress. These results add evidence on the possible Ni2+ induced - ER stress mainly associated with insoluble NCC. In this scenario, we also show how protein degradation mediated by ubiquitination seems to play key roles in cellular responses to Ni.
Insights
Nickel compounds are carcinogens, and this study reveals their molecular mechanisms. Nickel exposure triggers oxidative stress and endoplasmic reticulum stress, with Nrf2 protein playing a key role in cellular defense and protein degradation.
Area of Science:
- Toxicology
- Molecular Biology
- Bioinformatics
Background:
- Nickel and nickel-containing compounds (NCC) are recognized human carcinogens.
- The precise molecular mechanisms underlying nickel-induced malignant transformation are not fully understood.
- Proposed mechanisms involve the modulation of enzymatic pathways crucial for cellular defense against oxidative damage, with Nuclear factor-erythroid 2 related factor 2 (Nrf2) as a central regulator.
Purpose of the Study:
- To investigate the role of proteins in the Nrf2-mediated response to nickel and NCC exposure.
- To construct and analyze an interactome network of nickel-containing compounds and proteins.
- To identify key biological processes and molecular players involved in cellular responses to nickel.
Main Methods:
- Utilized the STITCH and STRING databases to design an interactome network.
- Analyzed the nickel-containing compound-protein interactome (NCPI) using MCODE for module detection.
- Determined network centralities with CentiScape and assessed biological processes using BiNGO within Cytoscape.
Main Results:
- Water-soluble NiSO4 and insoluble Ni3S2 showed the highest connectivity with proteins in the NCPI network.
- Nrf2 emerged as a highly relevant protein, involved in multiple protein complexes across different network clusters.
- Ontological analysis highlighted processes related to unfolded protein response (UPR) and endoplasmic reticulum (ER) stress within a key network cluster.
Conclusions:
- Cellular responses to NCC exposure, including oxidative stress, inflammation, and apoptosis, were comparable.
- Nrf2 plays a centralized role in cellular responses, particularly in complexes associated with ER stress.
- Evidence suggests Ni2+ induces ER stress, especially with insoluble NCC, and highlights the role of ubiquitination in protein degradation during cellular response to nickel.
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