N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

https://scholarlypublications.universiteitleiden.nl/access/item%3A3006385/view

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

SAM domain and HD domain containing protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that inhibits retroviruses by depleting intracellular deoxynucleotide triphosphates (dNTPs) in non-cycling myeloid cells. Although SAMHD1 is expressed ubiquitously throughout the human body, the molecular mechanisms regulating its enzymatic activity and function in non-immune cells are relatively unexplored. Here, we demonstrate that the dNTPase activity of SAMHD1 is regulated by acetylation, which promotes cell cycle progression in cancer cells. SAMHD1 is acetylated at residue lysine 405 (K405) in vitro and in vivo by an acetylatransferase, arrest defective protein 1 (ARD1). Acetylated SAMHD1 wildtype proteins have enhanced dNTPase activity in vitro, whereas non-acetylated arginine substituted mutants (K405R) do not. K405R mutant expressing cancer cells have reduced G1/S transition and slower proliferation compared to wildtype. SAMHD1 acetylation levels are strongest during the G1 phase, indicating a role during G1 phase. Collectively, these findings suggest that SAMHD1 acetylation enhances its dNTPase activity and promotes cancer cell proliferation. Therefore, SAMHD1 acetylation may be a potent therapeutic target for cancer treatment.

SAMHD1 acetylation enhances its deoxynucleotide triphosphohydrolase activity and promotes cancer cell proliferation

NAA10-related syndrome is an X-linked condition with a broad spectrum of findings ranging from a severe phenotype in males with p.Ser37Pro in NAA10, originally described as Ogden syndrome, to the milder NAA10-related intellectual disability found with different variants in both males and females. Although developmental impairments/intellectual disability may be the presenting feature (and in some cases the only finding), many individuals have additional cardiovascular, growth, and dysmorphic findings that vary in type and severity. Therefore, this set of disorders has substantial phenotypic variability and, as such, should be referred to more broadly as NAA10-related syndrome. NAA10 encodes an enzyme NAA10 that is certainly involved in the amino-terminal acetylation of proteins, alongside other proposed functions for this same protein. The mechanistic basis for how variants in NAA10 lead to the various phenotypes in humans is an active area of investigation, some of which will be reviewed herein.

/pdf/naa10-related-syndrome-73qwzes5h1.pdf

NAA10-related syndrome

Background N-α-acetyltransferase 10 protein (Naa10p) is a potential prognostic biomarker that modulates the phenotypes of several cancer types. Carcinoembryonic antigen (CEA) is currently the most well-known biomarker for the detection of epithelial malignancies. Our objective was to evaluate the clinical value of Naa10p, CEA, and their combined detection for diagnosis of oral squamous cell carcinoma (OSCC). Methods This study included 202 individuals: 112 patients with OSCC, 30 patients with oral premalignant lesions (OPMLs), and 60 cancer-free and without OPML patients as control. Naa10p and CEA were determined in serum and saliva samples utilizing enzyme-linked immunosorbent assays. Results Salivary and serum levels of Naa10p and CEA in OSCC patients were significantly higher than those detected in OPML and the control groups, although patients with OPMLs also showed increased salivary and serum Naa10p and CEA levels as compared to the control group. Salivary Naa10p level in OSCC patients is correlated with the degree of differentiation and lymph node metastasis, and serum Naa10p level is specifically correlated with patient age. Additionally, salivary CEA level is correlated with the clinical stage and lymph node metastasis, whereas serum CEA level is correlated with lymph node metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value of combined detection were greater than any single detection. Conclusions Combined use of salivary Naa10p and CEA as tumor markers for OSCC was more sensitive than serum Naa10p and CEA. These results indicated that combined detection of salivary Naa10p and CEA improved diagnostic performance and early detection rate for OSCC.

Clinical value of Naa10p and CEA levels in saliva and serum for diagnosis of oral squamous cell carcinoma.

N-α-acetyltransferase 10 protein promotes metastasis by stabilizing matrix metalloproteinase-2 protein in human osteosarcomas

Background: Human arrest defective 1 protein (ARD1), as a N-terminal acetyltransferase, has been reported to play a crucial role in tumorigenesis, but the results are somewhat controversial. To explore the clinical and pathological significance of ARD1 in breast tumorigenesis, we analyzed ARD1 status in multiple types of breast disease. Methods: The expression of ARD1 protein was assessed by immunohistochemistry in 356 cases including 82 invasive ductal carcinomas (IDC), 159 fibroadenomas, 66 hyperplasia of mammary glands, 19 inflammatory breast disease, 30 breast cysts, and in 29 postoperative treatment patients. We assessed the relationship of ARD1 protein with clinical and pathological characteristics using χ2 test. Results: ARD1 protein was observed at 61.0% (50/82), 54.7% (87/159), 37.9% (25/66), 36.8% (7/19) in IDC, fibroadenoma, hyperplasia, and inflammation, respectively, and less than 30.0% for breast cyst. Thus, high ARD1 expression correlated with breast cancer (relative risk = 1.32, P < 0.005). Moreover, the level of ARD1 protein in carcinoma patients was distinctly related to lymph node metastasis and ER status, with 94.0% (47/50) as copmpared to 6.0% (3/50) in metastatic and non-metastatic (P < 0.001), and 84.0% (42/50) and 16.0% (8/50) for ER + and ER - (P < 0.01), respectively. In addition, the level of ARD1 appeared to have potential for evaluation of prognosis in breast cancer patients after postoperative therapy. Conclusions: These results suggest that ARD1 expression may be as a potential target for exploring the mechanism of breast cancer metastasic to lymph nodes and hormone-responsive regulation.

Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.

Background: Clinical investigations repurposing a disintegrin and metalloproteases 10 (ADAM10) as metastatic and thrombus marker have achieved encouraging results, but the mechanism behind this association remains unclear. Methods: This study was carried out in NingXia and Wuhan, China from 2017 to 2021. The effects of ADAM10 expression on the metastatic and thrombus-associated genes: tissue factor (TF), P-selectin glycoprotein ligand-1 (PSGL-1), cathepsin G (CTSG) and mucin 1 (MUC1) were examined by immunofluorescence, qRTPCR and Western blotting analysis. Metastatic and thrombotic behaviors were evaluated using NODSCID mouse model. Results: The ADAM10 expression controlled the migration and invasion of pancreatic carcinoma cell-1(PANC-1), and significantly regulated the metastatic and thrombus-associated genes (P<0.05). ADAM10 and MUC1 were regulated and aberrantly expressed by a dependent mechanism. Moreover, ADAM10 expression induced the progression of adenocarcinoma cells and thrombus formation in vivo. Conclusion: Regulation of ADAM10 expression in cancer cells might effectively pave the way for a more potent anti-metastatic and anti-thrombotic approach and could regulate the invasion and migration of cancer cells.

https://doi.org/10.18502/ijph.v51i8.10262

A Disintegrin and Metalloprotease 10 Expressions Modulate Potential Metastatic and Thrombus Formation in Pancreatic Carcinoma

P75 pan‐neurotrophin receptor (p75NTR) is an important receptor for the role of neurotrophins in survival and death of neurons during development and after nerve injury. Our previous research found that the precursor of brain‐derived neurotrophic factor (proBDNF) regulates pain as an inflammatory mediator. The current understanding of the role of proBDNF/p75NTR signaling pathway in inflammatory arthritis pain and rheumatoid arthritis (RA) is unclear. We recruited 20 RA patients, 20 healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of proBDNF and p75NTR in synovial membrane were performed and evaluated. We next examined the mRNA and protein expression of proBDNF/p75NTR signaling pathway in peripheral blood mononuclear cells (PBMCs) and synovial tissue. ELISA and flow cytometry were assessed between the blood of RA patients and HD. To induce RA, collagen‐induced arthritis (CIA) were induced in mice. We found over‐synovitis of RA synovial membrane compared to OA controls in histologic sections. P75NTR and sortilin mRNA, and proBDNF protein level were significantly increased in PBMCs of RA patients compared with the HD. Consistently, ELISA showed that p75NTR, sortilin, tumor necrosis factor α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and interleukin‐10 (IL‐10) levels in the serum of RA patients were increased compared with HD and p75NTR, sortilin were positively correlated with Disease Activity Score in 28 joints (DAS28). In addition, using flow cytometry we showed that the increased levels of proBDNF and p75NTR characterized in CD4+ and CD8+ T cells of RA patients were subsequently reversed with methotrexate (MTX) treatment. Furthermore, we found pathological changes, inflammatory pain, upregulation of the mRNA and protein expression of proBDNF/p75NTR signaling pathway, and upregulation of inflammatory cytokines in spinal cord using a well‐established CIA mouse model. We showed intravenous treatment of recombinant p75ECD‐Fc that biologically blocked all inflammatory responses and relieved inflammatory pain of animals with CIA. Our findings showed the involvement of proBDNF/p75NTR pathway in the RA inflammatory response and how blocking it with p75ECD‐Fc may be a promising therapeutic treatment for RA.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1096/fj.202101558R

proBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines

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Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.

A Disintegrin and Metalloprotease 10 Expressions Modulate Potential Metastatic and Thrombus Formation in Pancreatic Carcinoma

proBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines