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2.
Ann Agric Environ Med ; 31(2): 306-310, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38940118

RESUMEN

The NAA10 gene encodes N-alpha-acetyltransferase 10 which plays an important role in cell growth, differentiation, DNA damage, metastasis, apoptosis, stress response and autophagy. Defects in the NAA10 gene correlate with the diagnosis of NAA10-related syndrome (Ogden syndrome). The most common symptoms of NAA10-related syndrome are: global developmental delay, non-verbal or limited speech, autism spectrum disorder, feeding difficulties, motor delay, muscle tone disturbances, and long QT syndrome. To-date, there are about 100 patients who have been reported with this condition. The case report presents the clinical study of a girl aged 4 years and 3 months diagnosed with Ogden syndrome. She had many characteristic features of the disorder, as well as precocious puberty. This girl represents the case of a patient with p.Arg83Cys mutation in NAA10 gene as well as precocious puberty.


Asunto(s)
Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Pubertad Precoz , Humanos , Femenino , Pubertad Precoz/genética , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Preescolar , Mutación
3.
PLoS One ; 19(5): e0301328, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38713657

RESUMEN

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.


Asunto(s)
Ratones Noqueados , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Animales , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Ratones , Femenino , Masculino , Fenotipo , Antecedentes Genéticos , Herencia Materna/genética , Ratones Endogámicos C57BL
4.
Am J Med Genet A ; 194(9): e63651, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38747166

RESUMEN

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland-3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland-3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland-3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub-domain analysis found the decline to be present across all modalities. In addition, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status, and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.


Asunto(s)
Convulsiones , Humanos , Convulsiones/genética , Convulsiones/fisiopatología , Convulsiones/terapia , Femenino , Masculino , Niño , Preescolar , Adulto , Lactante , Adolescente , Discapacidad Intelectual/genética , Adulto Joven , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/terapia , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa A N-Terminal/genética , Fenotipo
5.
Plant Physiol ; 195(4): 3097-3118, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-38588051

RESUMEN

In humans and plants, 40% of the proteome is cotranslationally acetylated at the N-terminus by a single Nα-acetyltransferase (Nat) termed NatA. The core NatA complex is comprised of the catalytic subunit Nα-acetyltransferase 10 (NAA10) and the ribosome-anchoring subunit NAA15. The regulatory subunit Huntingtin Yeast Partner K (HYPK) and the acetyltransferase NAA50 join this complex in humans. Even though both are conserved in Arabidopsis (Arabidopsis thaliana), only AtHYPK is known to interact with AtNatA. Here we uncover the AtNAA50 interactome and provide evidence for the association of AtNAA50 with NatA at ribosomes. In agreement with the latter, a split-luciferase approach demonstrated close proximity of AtNAA50 and AtNatA in planta. Despite their interaction, AtNatA/HYPK and AtNAA50 exerted different functions in vivo. Unlike NatA/HYPK, AtNAA50 did not modulate drought tolerance or promote protein stability. Instead, transcriptome and proteome analyses of a novel AtNAA50-depleted mutant (amiNAA50) implied that AtNAA50 negatively regulates plant immunity. Indeed, amiNAA50 plants exhibited enhanced resistance to oomycetes and bacterial pathogens. In contrast to what was observed in NatA-depleted mutants, this resistance was independent of an accumulation of salicylic acid prior to pathogen exposure. Our study dissects the in vivo function of the NatA interactors HYPK and NAA50 and uncovers NatA-independent roles for NAA50 in plants.


Asunto(s)
Acetiltransferasas , Proteínas de Arabidopsis , Arabidopsis , Acetiltransferasa E N-Terminal , Inmunidad de la Planta , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/microbiología , Arabidopsis/metabolismo , Arabidopsis/enzimología , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa A N-Terminal/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Inmunidad de la Planta/genética , Pseudomonas syringae/fisiología , Pseudomonas syringae/patogenicidad , Ácido Salicílico/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo
6.
Pathol Res Pract ; 255: 155191, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38340582

RESUMEN

INTRODUCTION: We aimed to investigate the expression and prognostic role of NAA10 in clear cell renal cell carcinoma (ccRCC). MATERIAL AND METHODS: We performed a gene expression and survival analysis based on the human cancer genome atlas database of ccRCC patients (TCGA-KIRC). RESULTS: The patients in the TCGA-KIRC (n = 537) were divided into two subgroups: NAA10-low and NAA10-high expression groups. NAA10-high ccRCC exhibited higher T stages (p = 0.002), a higher frequency of distant metastasis (p = 0.018), more advanced AJCC stages (p < 0.001), a lower overall survival time (p = 0.036), and a lower survival rate (p < 0.001). NAA10-high ccRCC was associated with increased activity of non-specific oncogenic pathways, including oxidative phosphorylation (p < 0.001) and cell cycle progression [G2 to M phase transition (p = 0.045) and E2F targets (p < 0.001)]. Additionally, the NAA10-high tumors showed reduced apoptosis via TRIAL pathways (p < 0.001) and increased levels of activity that promoted epithelial-mesenchymal transition (p = 0.026) or undifferentiation (p = 0.01). In ccRCC, NAA10 expression was found to be a negative prognostic factor in both non-metastatic (p < 0.001) and metastatic tumors (p = 0.032). CONCLUSIONS: In ccRCC, NAA10 expression was shown to be a negative prognostic factor related to tumor progression rather than tumor initiation, and high NAA10 expression promoted epithelial-mesenchymal transition and undifferentiation.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Transición Epitelial-Mesenquimal/genética , Expresión Génica , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/genética
9.
Biochim Biophys Acta Rev Cancer ; 1878(6): 188973, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37659460

RESUMEN

Nα-acetyltransferase 10 protein (Naa10p) is known as the catalytic subunit of N-terminal acetyltransferases A (NatA) complex, associating with Naa15p to acetylate N-termini of the human proteome. Recent investigations have unveiled additional functions for Naa10p, encompassing lysine ε-acetylation and acetyltransferase-independent activities. Its pleiotropic roles have been implicated in diverse physiological and pathological contexts. Emerging evidence has implicated Naa10p in cancer progression, demonstrating dual attributes as an oncogene or a tumor suppressor contingent on the cancer type and acetyltransferase activity context. In this comprehensive review, we present a pan-cancer analysis aimed at elucidating the intricacies underlying Naa10p dysregulation in cancer. Our findings propose the potential involvement of c-Myc as a modulatory factor influencing Naa10p expression. Moreover, we provide a consolidated summary of recent advancements in understanding the intricate molecular underpinnings through which Naa10p contributes to cancer cell proliferation and metastasis. Furthermore, we delve into the multifaceted nature of Naa10p's roles in regulating cancer behaviors, potentially attributed to its interactions with a repertoire of partner proteins. Through an exhaustive exploration of Naa10p's functions, spanning its acetylation activity and acetyltransferase-independent functionalities, this review offers novel insights with implications for targeted therapeutic strategies involving this pivotal protein in the realm of cancer therapeutics.


Asunto(s)
Acetiltransferasas , Neoplasias , Humanos , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Procesamiento Proteico-Postraduccional , Neoplasias/tratamiento farmacológico , Neoplasias/genética
10.
J Neuropathol Exp Neurol ; 82(7): 650-658, 2023 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-37253389

RESUMEN

NAA10 is a novel biomarker of cancer progression. The oncogenic and biological mechanisms of NAA10 in human malignancies are controversial and remain to be elucidated. Herein, we investigated the biological and clinicopathological implications of NAA10 gene expression in adult gliomas. We collected data from The Human Cancer Genome Atlas (TCGA) database, including patients from TCGA-GBM and TCGA-LGG projects. In total, there were 666 patients from the 2 projects (513 and 153 from TCGA-LGG and TCGA-GBM, respectively). Different analyses (pathway, DNA methylation, and survival analyses) require further specific case eliminations. Based on NAA10 expression, we divided 666 tumors into 2 subgroups: NAA10-high and NAA10-low glioma. There were higher activities of cell proliferation, metabolic reprogramming, DNA repair, angiogenesis, epithelial-mesenchymal transition, TNF-α, IL6/JAK/STAT6, mTORC1 signaling, and MYC targets in NAA10-high glioma, while P53, TGF-ß, Wnt, and Hedgehog pathways were highly expressed by NAA10-low gliomas. t-distributed stochastic neighbors embedding dimension reduction of DNA methylation also showed a high distribution of NAA10-high gliomas in distinct clusters. Survival analyses showed that high NAA10 expression was an independent prognostic factor. NAA10 expression dictated epigenetic, genetic, and clinicopathological differences in adult glioma. Further studies are required to investigate the detailed NAA10 oncogenic mechanisms and to validate NAA10 immunohistochemistry.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Adulto , Neoplasias Encefálicas/patología , Proteínas Hedgehog/genética , Glioma/patología , Metilación de ADN , Epigénesis Genética , Pronóstico , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo
11.
Eur J Hum Genet ; 31(7): 824-833, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37130971

RESUMEN

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Microftalmía , Humanos , Femenino , Síndrome , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Genotipo , Discapacidad Intelectual/genética , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo
12.
Am J Med Genet A ; 191(5): 1293-1300, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36810866

RESUMEN

Our study of 61 children with NAA10-related neurodevelopmental syndrome, an X-linked disorder due to NAA10 gene variants, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure-to-thrive diagnostic range; however, dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with NAA10-related neurodevelopmental syndrome includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in NAA10-related neurodevelopmental syndrome probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G-tube or GJ-tube fed probands demonstrates that G/GJ-tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if NAA10-related neurodevelopmental syndrome children are not tracking above the failure to thrive (FTT) range past 1 year of age despite such efforts, the treating physicians should be consulted regarding possibly undergoing G-tube placement to avoid prolonged growth failure. If G-tubes are not immediately inducing weight gain after insertion, recommendations could include altering formula, increasing caloric input, or exchanging a G-tube for a GJ-tube by means of a minimally invasive procedure.


Asunto(s)
Nutrición Enteral , Reflujo Gastroesofágico , Niño , Humanos , Nutrición Enteral/métodos , Gastrostomía/métodos , Reflujo Gastroesofágico/cirugía , Síndrome , Insuficiencia de Crecimiento/genética , Aumento de Peso , Variación Biológica Poblacional , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal
13.
Cell Death Dis ; 13(11): 995, 2022 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-36433943

RESUMEN

N-α-acetyltransferase 10 protein, Naa10p, is involved in various cellular functions impacting tumor progression. Due to its capacity to acetylate a large spectrum of proteins, both oncogenic and tumor-suppressive roles of Naa10p have been documented. Here, we report an oncogenic role of Naa10p in promoting metastasis of esophageal cancer. NAA10 is more highly expressed in esophageal cancer tissues compared to normal tissues. Higher NAA10 expression also correlates with poorer survival of esophageal cancer patients. We found that NAA10 expression was transcriptionally regulated by the critical oncogene c-Myc in esophageal cancer. Furthermore, activation of the c-Myc-Naa10p axis resulted in upregulated cell invasiveness of esophageal cancer. This increased cell invasiveness was also elucidated to depend on the enzymatic activity of Naa10p. Moreover, Naa10p cooperated with Naa15p to interact with the protease inhibitor, PAI1, and prevent its secretion. This inhibition of PAI1 secretion may derive from the N-terminal acetylation effect of the Naa10p/Naa15p complex. Our results establish the significance of Naa10p in driving metastasis in esophageal cancer by coordinating the c-Myc-PAI1 axis, with implications for its potential use as a prognostic biomarker and therapeutic target for esophageal cancer.


Asunto(s)
Neoplasias Esofágicas , Humanos , Acetilación , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/fisiopatología , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo
15.
Sci Adv ; 8(24): eabn6153, 2022 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-35704578

RESUMEN

In humans, the Huntingtin yeast partner K (HYPK) binds to the ribosome-associated Nα-acetyltransferase A (NatA) complex that acetylates ~40% of the proteome in humans and Arabidopsis thaliana. However, the relevance of HsHYPK for determining the human N-acetylome is unclear. Here, we identify the AtHYPK protein as the first in vivo regulator of NatA activity in plants. AtHYPK physically interacts with the ribosome-anchoring subunit of NatA and promotes Nα-terminal acetylation of diverse NatA substrates. Loss-of-AtHYPK mutants are remarkably resistant to drought stress and strongly resemble the phenotype of NatA-depleted plants. The ectopic expression of HsHYPK rescues this phenotype. Combined transcriptomics, proteomics, and N-terminomics unravel that HYPK impairs plant metabolism and development, predominantly by regulating NatA activity. We demonstrate that HYPK is a critical regulator of global proteostasis by facilitating masking of the recently identified nonAc-X2/N-degron. This N-degron targets many nonacetylated NatA substrates for degradation by the ubiquitin-proteasome system.


Asunto(s)
Arabidopsis , Acetiltransferasa A N-Terminal , Acetilación , Acetiltransferasas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Proteostasis
16.
Genes (Basel) ; 13(3)2022 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-35328089

RESUMEN

Variants in NAA15 are closely related to neurodevelopmental disorders (NDDs). In this study, we investigated the spectrum and clinical features of NAA15 variants in a Chinese NDD cohort of 769 children. Four novel NAA15 pathogenic variants were detected by whole-exome sequencing, including three de novo variants and one maternal variant. The in vitro minigene splicing assay confirmed one noncanonical splicing variant (c.1410+5G>C), which resulted in abnormal mRNA splicing. All affected children presented mild developmental delay, and catch-up trajectories were noted in three patients based on their developmental scores at different ages. Meanwhile, the literature review also showed that half of the reported patients with NAA15 variants presented mild/moderate developmental delay or intellectual disability, and possible catch-up sign was indicated for three affected patients. Taken together, our study expanded the spectrum of NAA15 variants in NDD patients. The affected patients presented mild developmental delay, and possible catch-up developmental trajectories were suggested. Studying the natural neurodevelopmental trajectories of NDD patients with pathogenic variants and their benefits from physical rehabilitations are needed in the future for precise genetic counseling and clinical management.


Asunto(s)
Discapacidad Intelectual , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Trastornos del Neurodesarrollo , Pueblo Asiatico , Niño , Estudios de Cohortes , Humanos , Discapacidad Intelectual/genética , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/genética , Trastornos del Neurodesarrollo/patología , Secuenciación del Exoma/métodos
17.
Nat Commun ; 13(1): 810, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-35145090

RESUMEN

N-terminal protein acetylation (NTA) is a prevalent protein modification essential for viability in animals and plants. The dominant executor of NTA is the ribosome tethered Nα-acetyltransferase A (NatA) complex. However, the impact of NatA on protein fate is still enigmatic. Here, we demonstrate that depletion of NatA activity leads to a 4-fold increase in global protein turnover via the ubiquitin-proteasome system in Arabidopsis. Surprisingly, a concomitant increase in translation, actioned via enhanced Target-of-Rapamycin activity, is also observed, implying that defective NTA triggers feedback mechanisms to maintain steady-state protein abundance. Quantitative analysis of the proteome, the translatome, and the ubiquitome reveals that NatA substrates account for the bulk of this enhanced turnover. A targeted analysis of NatA substrate stability uncovers that NTA absence triggers protein destabilization via a previously undescribed and widely conserved nonAc/N-degron in plants. Hence, the imprinting of the proteome with acetylation marks is essential for coordinating proteome stability.


Asunto(s)
Acetiltransferasas/metabolismo , Plantas/metabolismo , Proteoma/metabolismo , Acetilación , Acetiltransferasas/genética , Animales , Arabidopsis/metabolismo , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Procesamiento Proteico-Postraduccional , Proteoma/genética , Ribosomas/metabolismo
18.
Proteomics Clin Appl ; 16(3): e2100081, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35182098

RESUMEN

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is one of the most common and serious malignancies in China. However, the exact mechanisms of tumor progression are still unclear. Thus, identifying biomarkers for early diagnosis, prognostic and recurrence assessment of ESCC is necessary. EXPERIMENTAL DESIGN: iTRAQ was used to identify differentially expressed proteins (DEPs) in tumor tissues. N-alpha-acetyltransferase 10 (NAA10) is confirmed and validated by immunohistochemistry and western blotting. Furthermore, the effects of NAA10 on TE-1 cells were detected by CCK-8, colonies formation, anchorage-independent growth in soft agar, migration and transwell assays. LinkedOmics was used to identify differential gene expression with NAA10 and to analyze Gene Ontology and KEGG pathways. Coexpression gene network was conducted by the STRING database and Cytoscape software (MCODE plug-in). RESULTS: 516 DEPs were identified. NAA10 was downregulated in cancer tissues and selected for further confirmed. Furthermore, NAA10 can inhibit proliferation and tumorigenesis, and suppress migration and invasion of TE-1. Functional network analysis suggested that NAA10 regulates the ribosome pathways involving eight ribosomal proteins. CONCLUSION AND CLINICAL RELEVANCE: These findings clearly demonstrated that NAA10 is a tumor suppressor and novel potential biomarker for ESCC, laying a foundation for further study of the role of NAA10 in carcinogenesis.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Cromatografía Liquida , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasas N-Terminal/genética , Acetiltransferasas N-Terminal/metabolismo , Espectrometría de Masas en Tándem
19.
Hum Genet ; 141(8): 1355-1369, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35039925

RESUMEN

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.


Asunto(s)
Discapacidad Intelectual , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Acetilación , Genes Ligados a X , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo
20.
Life Sci Alliance ; 5(2)2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34764209

RESUMEN

N-terminal acetylation is a prominent protein modification, and inactivation of N-terminal acetyltransferases (NATs) cause protein homeostasis stress. Using multiplexed protein stability profiling with linear ubiquitin fusions as reporters for the activity of the ubiquitin proteasome system, we observed increased ubiquitin proteasome system activity in NatA, but not NatB or NatC mutants. We find several mechanisms contributing to this behavior. First, NatA-mediated acetylation of the N-terminal ubiquitin-independent degron regulates the abundance of Rpn4, the master regulator of the expression of proteasomal genes. Second, the abundance of several E3 ligases involved in degradation of UFD substrates is increased in cells lacking NatA. Finally, we identify the E3 ligase Tom1 as a novel chain-elongating enzyme (E4) involved in the degradation of linear ubiquitin fusions via the formation of branched K11, K29, and K48 ubiquitin chains, independently of the known E4 ligases involved in UFD, leading to enhanced ubiquitination of the UFD substrates.


Asunto(s)
Acetiltransferasa A N-Terminal/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Acetilación , Proteínas Fúngicas/metabolismo , Regulación Fúngica de la Expresión Génica , Acetiltransferasa A N-Terminal/química , Acetiltransferasa A N-Terminal/genética , Regiones Promotoras Genéticas , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteolisis , Ribonucleoproteínas/metabolismo , Transducción de Señal , Especificidad por Sustrato , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
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