Unveiling the human nitroproteome: Protein tyrosine nitration in cell signaling and cancer

Griswold-Prenner, Irene; Kashyap, Arun K.; Mazhar, Sahar; Hall, Zach W.; Fazelinia, Hossein; Ischiropoulos, Harry

doi:10.1016/j.jbc.2023.105038

Cited by 19 publications

(8 citation statements)

References 192 publications

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“…This concords with our and other observations. Nitrotyrosine [reviews: (37) (38)](39-41, 49-52) and TTLL12 (11, 14-19) levels increase with tumour progression, suggesting that they are linked. However, the comparison is indirect, since this nitrotyrosine is mainly found in proteins as a result of chemical modification during oxidative and nitrosative stress, rather than as free nitrotyrosine that is required for ligation to the C-terminus of detyrosinated α-tubulin.…”

Section: Discussionmentioning

confidence: 99%

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

Deshpande,

Brants,

Wasylyk

et al. 2023

Preprint

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Tubulin tyrosine ligase 12 (TTLL) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTMcollection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 μM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.

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Section: Discussionmentioning

confidence: 99%

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

Deshpande,

Brants,

Wasylyk

et al. 2023

Preprint

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“…Tyrosine nitration is involved in several RNS-related biological processes such as oxidative stress responses, cell signaling, and cell death . It is known to be associated with aging, cancers, atherosclerosis, and neurodegenerative diseases. − …”

Section: Tyrosine Modificationsmentioning

confidence: 99%

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Gan,

Fan

2024

Chem. Rev.

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Post-translational modifications (PTMs) endow proteins with new properties to respond to environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds of distinct types of PTMs have been observed in a wide range of proteins from bacteria, archaea, and eukarya. To identify the roles of these PTMs, scientists have applied various approaches. However, high dynamics, low stoichiometry, and crosstalk between PTMs make it almost impossible to obtain homogeneously modified proteins for characterization of the site-specific effect of individual PTM on target proteins. To solve this problem, the genetic code expansion (GCE) strategy has been introduced into the field of PTM studies. Instead of modifying proteins after translation, GCE incorporates modified amino acids into proteins during translation, thus generating site-specifically modified proteins at target positions. In this review, we summarize the development of GCE systems for orthogonal translation for site-specific installation of PTMs.

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“…Nitrosylation of proteins by tyrosine residues, facilitated by ONOO-, can have significant functional consequences, as it suppresses tyrosine phosphorylation and disrupts certain signal transduction pathways within the cell [183,243]. The balance between NO and the thiol-disulfide system is a critical factor determining the subsequent fate of neurons under ischemic conditions, particularly the mode of cell death.…”

Section: No and Cerebral Ischemiamentioning

confidence: 99%

Nitric Oxide in the Mechanisms of Cell Death and Cytoprotection

Belenichev,

Popazova,

Bukhtiyarova

et al. 2024

Preprint

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The regulation of cell death is a fundamental issue in cell biology and continues to be intensely investigated worldwide. The significance of research in this field persists because understanding the determinants of cell lifespan directly impacts the maintenance of multicellular organism homeostasis and, consequently, is crucial for addressing biomedical challenges associated with various diseases. It is recognized that the initiation of cell death can be prompted by both specific signals (such as cytokines or hormones) and nonspecific stimuli, including radiation, temperature increase, or oxidants. When these factors affect a cell, numerous signaling pathways are triggered in the cell, leading to neutralization of the effects of their negative effects or, in case of irreparable damage, to cell elimination. This removal of damaged cells occurs through apoptosis or programmed cell death, a highly regulated process. Numerous signaling molecules participate in orchestrating the apoptotic process, many of which also govern other essential functions within the organism. Physiological factors capable of triggering the apoptotic program in cells include nitric oxide (NO), which serves as one of the key signaling molecules regulating the functions of the cardiovascular, nervous, and immune systems of the organism. The unique chemical nature of NO, along with its numerous intracellular targets and physiologically active redox forms, raises questions about the specific mechanisms through which NO exerts its damaging effects on cells. Utilizing pharmacological preparations- such as sources (donors) of exogenous nitric oxide- represents an approach to investigating the initiation and execution of the apoptotic program in sensitive target cells. Furthermore, this approach holds promise as a direction for discovering new selective drugs.

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Unveiling the human nitroproteome: Protein tyrosine nitration in cell signaling and cancer

Cited by 19 publications

References 192 publications

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

Novel inhibitors of TTLL12’s oncogenic potential that overcome suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Nitric Oxide in the Mechanisms of Cell Death and Cytoprotection

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