Quantitative proteome analysis of LAP1-deficient human fibroblasts: A pilot approach for predicting the signaling pathways deregulated in LAP1-associated diseases.
Bioinformatics; DNA repair; Mass spectrometry; Oxidative stress response; Protein synthesis; Proteomics; Proteostasis; Biophysics; Biochemistry; Cell Biology
Abstract :
[en] Lamina-associated polypeptide 1 (LAP1), a ubiquitously expressed nuclear envelope protein, appears to be essential for the maintenance of cell homeostasis. Although rare, mutations in the human LAP1-encoding TOR1AIP1 gene cause severe diseases and can culminate in the premature death of affected individuals. Despite there is increasing evidence of the pathogenicity of TOR1AIP1 mutations, the current knowledge on LAP1's physiological roles in humans is limited; hence, investigation is required to elucidate the critical functions of this protein, which can be achieved by uncovering the molecular consequences of LAP1 depletion, a topic that remains largely unexplored. In this work, the proteome of patient-derived LAP1-deficient fibroblasts carrying a pathological TOR1AIP1 mutation (LAP1 E482A) was quantitatively analyzed to identify global changes in protein abundance levels relatively to control fibroblasts. An in silico functional enrichment analysis of the mass spectrometry-identified differentially expressed proteins was also performed, along with additional in vitro functional assays, to unveil the biological processes that are potentially dysfunctional in LAP1 E482A fibroblasts. Collectively, our findings suggest that LAP1 deficiency may induce significant alterations in various cellular activities, including DNA repair, messenger RNA degradation/translation, proteostasis and glutathione metabolism/antioxidant response. This study sheds light on possible new functions of human LAP1 and could set the basis for subsequent in-depth mechanistic investigations. Moreover, by identifying deregulated signaling pathways in LAP1-deficient cells, our work may offer valuable molecular targets for future disease-modifying therapies for TOR1AIP1-associated nuclear envelopathies.
Disciplines :
Pediatrics
Author, co-author :
Pereira, Cátia D; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal
Espadas, Guadalupe; Center for Genomics Regulation, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain ; Universitat Pompeu Fabra, Barcelona, Spain
Martins, Filipa; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal
Bertrand, Anne T; Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; MDUK Oxford Neuromuscular Center, Department of Paediatrics, University of Oxford and NIHR Oxford Biomedical Research Center, Oxford, OX3 9DU, United Kingdom
Sabidó, Eduard; Center for Genomics Regulation, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain ; Universitat Pompeu Fabra, Barcelona, Spain
Chevalier, Philippe ; Université de Liège - ULiège > Département des sciences cliniques ; Université Claude Bernard Lyon 1, Lyon, France ; Hospices Civils de Lyon, Lyon, France
da Cruz E Silva, Odete A B; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal
Rebelo, Sandra ; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal
Language :
English
Title :
Quantitative proteome analysis of LAP1-deficient human fibroblasts: A pilot approach for predicting the signaling pathways deregulated in LAP1-associated diseases.
This work was financed by the Institute of Biomedicine (iBiMED)\u2014UIDP/04501/2020 and UIDB/04501/2020\u2014and the Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT) of the Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior, the COMPETE 2020 Program, the QREN and the European Union (Fundo Europeu de Desenvolvimento Regional). Authors acknowledge support from EPIC-XS, project number 823839, funded by the Horizon 2020 Program of the European Union. The proteomics analyses were performed in the Proteomics Unit from the Centre de Regulaci\u00F3 Gen\u00F2mica (CRG) and Universitat Pompeu Fabra (UPF). The CRG/UPF Proteomics Unit is part of the Spanish National Infrastructure for Omics Sciences (ICTS OmicsTech). Image acquisition was performed in the LiM facility of iBiMED, a node of Portuguese Platform of BioImaging (PPBI)\u2014POCI-01-0145-FEDER-02212. C.D.P. is the recipient of a PhD fellowship\u2014SFRH/BD/140310/2018 and COVID/BD/152982/2023\u2014co-funded by FCT of the Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior, the Centro 2020 Program and the European Union (Fundo Social Europeu).In this work, the experimental and bioinformatics results revealed alterations in the redox status and functioning of antioxidant defense systems in LAP1 E482A fibroblasts. We detected significantly elevated Nrf2 protein levels in LAP1 E482A versus control fibroblasts without prior exposure to stressful agents (Fig. 6d). A higher sensitivity to treatment with exogenous H2O2 (100 \u03BCM) was also observed in LAP1 E482A fibroblasts, as shown by a substantial Nrf2 accumulation in these cells that contrasts with the slight increase in Nrf2 protein levels in control fibroblasts (Fig. 6d). It is known that constitutively expressed Nrf2 is constantly degraded and maintains a low basal protein level in a physiological context; however, in response to oxidative/electrophilic stress, de novo synthesized Nrf2 is stabilized to activate the transcription of genes encoding cytoprotective antioxidant and detoxifying enzymes, such as nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) quinone oxidoreductase 1 (NQO1) [103]. This ROS-inducible enzyme is involved in the cellular defense against oxidative stress, for example by reducing ubiquinone, a constituent of the mitochondrial electron transport chain, to its antioxidant form [104] as well as scavenging ROS [105]. Interestingly, NQO1 is one of the upregulated proteins identified by LC\u2013MS/MS in LAP1 E482A fibroblasts (Fig. 2a; Supplementary Table S1), which is consistent with Nrf2 induction in a basal state (Fig. 6d). These data could indicate that the amount of ROS normally present in these cells may exceed a physiological level and cause oxidative stress, leading to hyperactivation of endogenous antioxidant mechanisms, like the Nrf2-mediated stress response, to shift the redox equilibrium back to a more reducing state. Our proteomics analysis also evidenced a deregulation of proteins implicated in glutathione metabolism, namely \u03B3-glutamyl transferase 5 (GGT5) and glutathione synthetase (GS), in LAP1 E482A fibroblasts (Fig. 4c; Supplementary Table S8). Glutathione is a potent antioxidant agent abundant in the cytosol, where it exists mostly in a reduced form (i.e. GSH) under homeostatic redox conditions; when this balance is perturbed by oxidants, glutathione is temporarily converted to an oxidized form (e.g. GSSG) while carrying out antioxidant functions that include, for instance, protecting thiol groups in proteins from permanent oxidation, neutralizing ROS and detoxifying xenobiotics [106]. The fact that GS, the enzyme that catalyzes the second and final step in glutathione synthesis [107], is upregulated in LAP1 E482A fibroblasts (Fig. 2a; Supplementary Table S1) points to a stimulation of glutathione production. In addition to de novo biosynthesis, another means to maintain an elevated intracellular concentration of glutathione is by enhancing the uptake of exogenous one, which can be promoted by GGT5 [108]. Its hydrolytic action initiates the extracellular degradation of glutathione S-conjugates, GSH and GSSG [109], releasing intermediates that are further metabolized so that precursor amino acids can be taken up by cells and reincorporated into glutathione [108]. So, the upregulation of GS and GGT5 in LAP1 E482A fibroblasts (Fig. 2a; Supplementary Table S1) may reflect an adaptive response to amplify the cells\u2019 capacity to replenish the glutathione pool in the intracellular milieu and maximize the redox potential when facing oxidative challenges, namely by supporting a higher activity of glutathione-dependent protective enzymes, as is the case of glutathione S-transferase \u03BC4 (GSTM4), another protein upregulated in these cells (Fig. 2a; Supplementary Table S1).This work was financed by the Institute of Biomedicine (iBiMED)\u2014UIDP/04501/2020 and UIDB/04501/2020\u2014and the Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT) of the Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior, the COMPETE 2020 Program, the QREN and the European Union (Fundo Europeu de Desenvolvimento Regional). Authors acknowledge support from EPIC-XS, project number 823839, funded by the Horizon 2020 Program of the European Union. The proteomics analyses were performed in the Proteomics Unit from the Centre de Regulaci\u00F3 Gen\u00F2mica (CRG) and Universitat Pompeu Fabra (UPF). The CRG/UPF Proteomics Unit is part of the Spanish National Infrastructure for Omics Sciences (ICTS OmicsTech). Image acquisition was performed in the LiM facility of iBiMED, a node of Portuguese Platform of BioImaging (PPBI)\u2013POCI-01-0145-FEDER-02212. C.D.P. is the recipient of a PhD fellowship\u2014SFRH/BD/140310/2018 and COVID/BD/152982/2023\u2014co-funded by FCT of the Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior, the Centro 2020 Program and the European Union (Fundo Social Europeu).
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