Multiple impacts of Naa10p on cancer progression: Molecular functions and clinical prospects.

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.

Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae.

Protein N-terminal (Nt) acetylation is one of the most abundant modifications in eukaryotes, covering ~50-80 % of the proteome, depending on species. Cells with defective Nt-acetylation display a wide array of phenotypes such as impaired growth, mating defects and increased stress sensitivity. However, the pleiotropic nature of these effects has hampered our understanding of the functional impact of protein Nt-acetylation. The main enzyme responsible for Nt-acetylation throughout the eukaryotic kingdom is the N-terminal acetyltransferase NatA. Here we employ a multi-dimensional proteomics approach to analyze Saccharomyces cerevisiae lacking NatA activity, which causes global proteome remodeling. Pulsed-SILAC experiments reveals that NatA-deficient strains consistently increase degradation of ribosomal proteins compared to wild type. Explaining this phenomenon, thermal proteome profiling uncovers decreased thermostability of ribosomes in NatA-knockouts. Our data are in agreement with a role for Nt-acetylation in promoting stability for parts of the proteome by enhancing the avidity of protein-protein interactions and folding.

Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.

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.

NAA10 overexpression dictates distinct epigenetic, genetic, and clinicopathological characteristics in adult gliomas.

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.

Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs).

BACKGROUND: Esophageal squamous carcinoma (ESCC) is a common malignancy that originates in the digestive tract. Lymph node metastasis (LNM) is a complicated process, and tumor lymphangiogenesis has been reported to be associated with the spread of tumor cells to lymph nodes (LNs), including in ESCC. However, little is currently known about the mechanisms involved in lymphangiogenesis in ESCC tumors. According to previous literature, we know that hsa_circ_0026611 expresses at a high level in serum exosomes of patients with ESCC and shows a close association with LNM and poor prognosis. However, details on the functions of circ_0026611 in ESCC remain unclear. We aim to explore the effects of circ_0026611 in ESCC cell-derived exosomes on lymphangiogenesis and its potential molecular mechanism. METHODS: We firstly examined how circ_0026611 may express in ESCC cells and exosomes by quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The potential effects circ_0026611 may exert on lymphangiogenesis in ESCC cell-derived exosomes were assessed afterward via mechanism experiments. RESULTS: circ_0026611 high expression pattern was confirmed in ESCC cells and exosomes. ESCC cell-derived exosomes promoted lymphangiogenesis by transferring circ_0026611. Besides, circ_0026611 interacted with N-α-acetyltransferase 10 (NAA10) to inhibit NAA10-mediated prospero homeobox 1 (PROX1) acetylation with subsequent ubiquitination and degradation. Furthermore, circ_0026611 was verified to promote lymphangiogenesis in a PROX1-mediated manner. CONCLUSIONS: Exosomal circ_0026611 inhibited PROX1 acetylation and ubiquitination to promote lymphangiogenesis in ESCC.

Naa10p promotes cell invasiveness of esophageal cancer by coordinating the c-Myc and PAI1 regulatory axis.

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.

HYPK promotes the activity of the Nα-acetyltransferase A complex to determine proteostasis of nonAc-X2/N-degron-containing proteins.

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.

UBA domain protein SUF1 interacts with NatA-complex subunit NAA15 to regulate thermotolerance in Arabidopsis.

During recovery from heat stress, plants clear away the heat-stress-induced misfolded proteins through the ubiquitin-proteasome system (UPS). In the UPS, the recognition of substrate proteins by E3 ligase can be regulated by the N-terminal acetyltransferase A (NatA) complex. Here, we determined that Arabidopsis STRESS-RELATED UBIQUITIN-ASSOCIATED-DOMAIN PROTEIN FACTOR 1 (SUF1) interacts with the NatA complex core subunit NAA15 and positively regulates NAA15. The suf1 and naa15 mutants are sensitive to heat stress; the NatA substrate N SNC1 is stabilized in suf1 mutant plants during heat stress recovery. Therefore, SUF1 and its interactor NAA15 play important roles in basal thermotolerance in Arabidopsis.

N-α-Acetyltransferase 10 inhibits invasion and metastasis of oral squamous cell carcinoma via regulating Pirh2-p53 signalling pathway.

N-α-Acetyltransferase 10 (NAA10) was reported to be involved in tumour invasion and metastasis in several of tumours. However, the role and mechanism of NAA10-mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Herein, our study showed that NAA10 inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, we demonstrated that there is a physical interaction between NAA10 and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, matrix metalloprotein-2 (MMP-2) and MMP-9. Therefore, NAA10 may function as a tumour metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis and might be a prognostic marker as well as a therapeutic target for OSCC.

OsHYPK-mediated protein N-terminal acetylation coordinates plant development and abiotic stress responses in rice.

N-terminal acetylation is one of the most common protein modifications in eukaryotes, and approximately 40% of human and plant proteomes are acetylated by ribosome-associated N-terminal acetyltransferase A (NatA) in a co-translational manner. However, the in vivo regulatory mechanism of NatA and the global impact of NatA-mediated N-terminal acetylation on protein fate remain unclear. Here, we identify Huntingtin Yeast partner K (HYPK), an evolutionarily conserved chaperone-like protein, as a positive regulator of NatA activity in rice. We found that loss of OsHYPK function leads to developmental defects in rice plant architecture but increased resistance to abiotic stresses, attributable to perturbation of the N-terminal acetylome and accelerated global protein turnover. Furthermore, we demonstrated that OsHYPK is also a substrate of NatA and that N-terminal acetylation of OsHYPK promotes its own degradation, probably through the Ac/N-degron pathway, which could be induced by abiotic stresses. Taken together, our findings suggest that the OsHYPK-NatA complex plays a critical role in coordinating plant development and stress responses by dynamically regulating NatA-mediated N-terminal acetylation and global protein turnover, which are essential for maintaining adaptive phenotypic plasticity in rice.

iTRAQ and two-dimensional-LC-MS/MS reveal NAA10 is a potential biomarker in esophageal squamous cell carcinoma.

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.

Cotranslational N-degron masking by acetylation promotes proteome stability in plants.

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.

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation.

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.

Up-regulation of ubiquitin-proteasome activity upon loss of NatA-dependent N-terminal acetylation.

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.

Acetilación N-terminal, acetiltransferasas y mutaciones en subunidad auxiliar NAA15 de N-terminal acetiltransferasa A, asociadas a discapacidad intelectual y trastorno del espectro autista: una revisión bibliográfica / N-terminal acetylation, acetyltransferases and variants in NAA15 auxiliary subunit of the N-terminal acetyltransferase A associated with intellectual disability and autism spectrum disorder: a literature review

Las N-terminal acetiltransferasas (NaT) son fundamentales en el desarrollo, funcionamiento y vida media celular, acetilando gran parte del proteoma humano. Entre las ocho NaT identificadas, N-terminal acetiltransferasa A (NaTA) acetila a un mayor número de sustratos, teniendo además un rol fundamental en el neurodesarrollo. Previamente, estudios han demostrado que mutaciones en la subunidad catalítica de NaTA, NAA10, se asocian con trastornos del neurodesarrollo. Sin embargo, nuevas líneas investigativas sugieren que mutaciones de la subunidad auxiliar, NAA15, también tendrían un rol importante en el desarrollo de estos trastornos. Esta revisión se realiza con el objetivo de recopilar evidencia sobre variantes de NAA15 relacionadas con Discapacidad Intelectual (DI) y Trastorno de Espectro Autista (TEA). Se consultaron fuentes actualizadas sobre acetilación N-terminal, NaT, DI y TEA y mutaciones reportadas de NAA15 y sus expresiones fenotípicas, publicadas entre 2011 y 2022. Se concluye que, aun cuando existe relación entre mutaciones de NAA15, DI y TEA, todavía es necesario esclarecer los mecanismos fisiopatológicos de estos trastornos, el rol de NaTA y el impacto de variantes de sus subunidades en las vías moleculares y el fenotipo, lo que se dificulta por razones que van desde la complejidad de estas vías hasta el elevado costo de análisis genéticos. Se sugiere continuar la investigación en esta área, para comprender las bases moleculares subyacentes a estos trastornos y el rol de las mutaciones en subunidades de NaTA, con el fin último de estudiar potenciales tratamientos que mejoren la calidad de vida de las personas con estos trastornos y sus familias.

Nt-acetyltransferases (NaT) are essential in cell development, function and half-life, catalyzing most of the human proteome. Among the eight NaTs identified, N-terminal acetyltransferase A (NaTA) acetylates a greater number of substrates, also having a fundamental role in neurodevelopment. Previously, studies have shown that mutations in the catalytic subunit of NaTA, NAA10, are associated with neurodevelopmental disorders. However, new research lines suggest that mutations of the NAA15 helper subunit also plays an important role in the development of these disorders. This review is carried out with the objective of gathering evidence on NAA15 variants related to Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). Updated sources on N-terminal acetylation, N-acetyltransferases, DI and TEA and reported mutations of NAA15 and their phenotypic expressions, published between 2011 and 2022 were consulted. It is concluded that even though there is a relationship between mutations of NAA15, ID and ASD exists, it is still necessary to clarify the pathophysiological mechanisms of these disorders, the role of NaTA and the impact of variants of its subunits in the molecular pathways and in the phenotype, for reasons ranging from the complexity of these pathways to the high cost of genetic testing. It is suggested to continue research in this area, to understand the molecular bases underlying these disorders and the role of mutations in NatA subunits, with the ultimate aim of studying potential treatments that improve the quality of life of people with these disorders and their families.

Hydroxylation of the Acetyltransferase NAA10 Trp38 Is Not an Enzyme-Switch in Human Cells.

NAA10 is a major N-terminal acetyltransferase (NAT) that catalyzes the cotranslational N-terminal (Nt-) acetylation of 40% of the human proteome. Several reports of lysine acetyltransferase (KAT) activity by NAA10 exist, but others have not been able to find any NAA10-derived KAT activity, the latter of which is supported by structural studies. The KAT activity of NAA10 towards hypoxia-inducible factor 1α (HIF-1α) was recently found to depend on the hydroxylation at Trp38 of NAA10 by factor inhibiting HIF-1α (FIH). In contrast, we could not detect hydroxylation of Trp38 of NAA10 in several human cell lines and found no evidence that NAA10 interacts with or is regulated by FIH. Our data suggest that NAA10 Trp38 hydroxylation is not a switch in human cells and that it alters its catalytic activity from a NAT to a KAT.

N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.

Huntington's disease (HD) is a neurodegenerative disorder caused by a poly-CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine tract in the N-terminal domain of the Huntingtin (Htt) protein product. Proteolytic fragments of the poly-glutamine-containing N-terminal domain form intranuclear aggregates that are correlated with HD. Post-translational modification of Htt has been shown to alter its function and aggregation properties. However, the effect of N-terminal Htt acetylation has not yet been considered. Here, we developed a bacterial system to produce unmodified or N-terminally acetylated and aggregation-inducible Htt protein. We used this system together with biochemical, biophysical, and imaging studies to confirm that the Htt N-terminus is an in vitro substrate for the NatA N-terminal acetyltransferase and show that N-terminal acetylation promotes aggregation. These studies represent the first link between N-terminal acetylation and the promotion of a neurodegenerative disease and implicates NatA-mediated Htt acetylation as a new potential therapeutic target in HD.

Charting the N-Terminal Acetylome: A Comprehensive Map of Human NatA Substrates.

N-terminal acetylation (Nt-acetylation) catalyzed by conserved N-terminal acetyltransferases or NATs embodies a modification with one of the highest stoichiometries reported for eukaryotic protein modifications to date. Comprising the catalytic N-alpha acetyltransferase (NAA) subunit NAA10 plus the ribosome anchoring regulatory subunit NAA15, NatA represents the major acetyltransferase complex with up to 50% of all mammalian proteins representing potential substrates. Largely in consequence of the essential nature of NatA and its high enzymatic activity, its experimentally confirmed mammalian substrate repertoire remained poorly charted. In this study, human NatA knockdown conditions achieving near complete depletion of NAA10 and NAA15 expression resulted in lowered Nt-acetylation of over 25% out of all putative NatA targets identified, representing an up to 10-fold increase in the reported number of substrate N-termini affected upon human NatA perturbation. Besides pointing to less efficient NatA substrates being prime targets, several putative NatE substrates were shown to be affected upon human NatA knockdown. Intriguingly, next to a lowered expression of ribosomal proteins and proteins constituting the eukaryotic 48S preinitiation complex, steady-state levels of protein N-termini additionally point to NatA Nt-acetylation deficiency directly impacting protein stability of knockdown affected targets.

Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway.

Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralog with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.

Naa10p and IKKα interaction regulates EMT in oral squamous cell carcinoma via TGF-ß1/Smad pathway.

Epithelial-mesenchymal transition (EMT) has been contributed to increase migration and invasion of cancer cells. However, the correlate of Naa10p and IKKα with EMT in oral squamous cell carcinoma (OSCC) is not yet fully understood. In our present study, we found N-α-acetyltransferase 10 protein (Naa10p) and IκB kinase α (IKKα) were abnormally abundant in oral squamous cell carcinoma (OSCC). Bioinformatic results indicate that the expression of Naa10p and IKKα is correlated with TGF-ß1/Smad and EMT-related molecules. The Transwell migration, invasion, qRT-PCR and Western blot assay indicated that Naa10p repressed OSCC cell migration, invasion and EMT, whereas IKKα promoted TGF-ß1-mediated OSCC cell migration, invasion and EMT. Mechanistically, Naa10p inhibited IKKα activation of Smad3 through the interaction with IKKα directly in OSCC cells after TGF-ß1 stimulation. Notably, knockdown of Naa10p reversed the IKKα-induced change in the migration, invasion and EMT-related molecules in OSCC cells after TGF-ß1 stimulation. These findings suggest that Naa10p interacted with IKKα mediates EMT in OSCC cells through TGF-ß1/Smad, a novel pathway for preventing OSCC.