Tyrosine nitration as a key event of signal transduction that regulates functional state of the cell

Sabadashka, Mariya; Nagalievska, Mariia; Sybirna, N. O.

doi:10.1002/cbin.11301

Cited by 24 publications

(13 citation statements)

References 124 publications

(181 reference statements)

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“…Possibly the differences in gene expression profile between NO donors and GSNO are due to differential redox status, which was not investigated and is beyond the scope of this study. In addition to S-nitrosylation, another NO-dependent post-translational modification is tyrosine nitration, which also plays an important role in regulating protein structure and activity (58)(59)(60). Nitration of tyrosine residues is classically produced by peroxynitrite, generated by the reaction of NO and oxygen radicals, associated with oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Majumdar

Choudhury

Manivannan

et al. 2022

Front. Cardiovasc. Med.

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Calcific aortic valve disease (CAVD) is an increasingly prevalent condition among the elderly population that is associated with significant morbidity and mortality. Insufficient understanding of the underlying disease mechanisms has hindered the development of pharmacologic therapies for CAVD. Recently, we described nitric oxide (NO) mediated S-nitrosylation as a novel mechanism for preventing the calcific process. We demonstrated that NO donor or an S-nitrosylating agent, S-nitrosoglutathione (GSNO), inhibits spontaneous calcification in porcine aortic valve interstitial cells (pAVICs) and this was supported by single-cell RNA sequencing (scRNAseq) that demonstrated NO donor and GSNO inhibited myofibroblast activation of pAVICs. Here, we investigated novel signaling pathways that are critical for the calcification of pAVICs that are altered by NO and GSNO by performing an in-depth analysis of the scRNA-seq dataset. Transcriptomic analysis revealed 1,247 differentially expressed genes in pAVICs after NO donor or GSNO treatment compared to untreated cells. Pathway-based analysis of the differentially expressed genes revealed an overrepresentation of the integrin signaling pathway, along with the Rho GTPase, Wnt, TGF-β, and p53 signaling pathways. We demonstrate that ITGA8 and VCL, two of the identified genes from the integrin signaling pathway, which are known to regulate cell-extracellular matrix (ECM) communication and focal adhesion, were upregulated in both in vitro and in vivo calcific conditions. Reduced expression of these genes after treatment with NO donor suggests that NO inhibits calcification by targeting myofibroblast adhesion and ECM remodeling. In addition, withdrawal of NO donor after 3 days of exposure revealed that NO-mediated transcriptional and translational regulation is a transient event and requires continuous NO exposure to inhibit calcification. Overall, our data suggest that NO and S-nitrosylation regulate the integrin signaling pathway to maintain healthy cell-ECM interaction and prevent CAVD.

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Majumdar

Choudhury

Manivannan

et al. 2022

Front. Cardiovasc. Med.

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“…In addition to the ERFVII-mediated NO signaling, the reactive nature of NO makes it to react with other molecules as a primary action. Such NO reaction with proteins ends with PTMs that include the S-nitrosylation of Cys ( Gupta et al, 2020 ) and, upon previous reaction with superoxide to form peroxynitrite ( Liaudet et al, 2009 ; Vandelle and Delledonne, 2011 ), the nitration of Tyr, Trp, and to a lesser extent also Phe and His ( Sabadashka et al, 2021 ). Besides peroxynitrite, the •NO 2 radical formed from nitrite through peroxidase-mediated oxidation under certain conditions is also an efficient nitrating agent of proteins ( Jones, 2012 ).…”

Section: Signaling Downstream No Sensing Involves Diverse Post-transl...mentioning

confidence: 99%

Protein Tyrosine Nitration in Plant Nitric Oxide Signaling

León

2022

Front. Plant Sci.

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Nitric oxide (NO), which is ubiquitously present in living organisms, regulates many developmental and stress-activated processes in plants. Regulatory effects exerted by NO lies mostly in its chemical reactivity as a free radical. Proteins are main targets of NO action as several amino acids can undergo NO-related post-translational modifications (PTMs) that include mainly S-nitrosylation of cysteine, and nitration of tyrosine and tryptophan. This review is focused on the role of protein tyrosine nitration on NO signaling, making emphasis on the production of NO and peroxynitrite, which is the main physiological nitrating agent; the main metabolic and signaling pathways targeted by protein nitration; and the past, present, and future of methodological and strategic approaches to study this PTM. Available information on identification of nitrated plant proteins, the corresponding nitration sites, and the functional effects on the modified proteins will be summarized. However, due to the low proportion of in vivo nitrated peptides and their inherent instability, the identification of nitration sites by proteomic analyses is a difficult task. Artificial nitration procedures are likely not the best strategy for nitration site identification due to the lack of specificity. An alternative to get artificial site-specific nitration comes from the application of genetic code expansion technologies based on the use of orthogonal aminoacyl-tRNA synthetase/tRNA pairs engineered for specific noncanonical amino acids. This strategy permits the programmable site-specific installation of genetically encoded 3-nitrotyrosine sites in proteins expressed in Escherichia coli, thus allowing the study of the effects of specific site nitration on protein structure and function.

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“…Finally, this post-translational modification may generate unmasking of epitopes triggering an immune response. Consequently, the accumulation of nitrated proteins in apoptotic and inflamed tissues due to oxidative stress may induce an autoimmune response aggravating the chronic inflammatory response ( Thomson et al, 2007 ; Abello et al, 2009 ; Sabadashka et al, 2021 ).…”

Section: Role Of Nitric Oxide System In Bronchial Epithelium and Related Diseasesmentioning

confidence: 99%

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

et al. 2021

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Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.

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Tyrosine nitration as a key event of signal transduction that regulates functional state of the cell

Cited by 24 publications

References 124 publications

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Single-cell RNA-sequencing analysis of aortic valve interstitial cells demonstrates the regulation of integrin signaling by nitric oxide

Protein Tyrosine Nitration in Plant Nitric Oxide Signaling

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

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