Advances of NAT10 in diseases: insights from dual properties as protein and RNA acetyltransferase

Abstract

N-acetyltransferase 10 (NAT10) is a member of the Gcn5-related N-acetyltransferase (GNAT) family and it plays a crucial role in various cellular processes, such as regulation of cell mitosis, post-DNA damage response, autophagy and apoptosis regulation, ribosome biogenesis, RNA modification, and other related pathways through its intrinsic protein acetyltransferase and RNA acetyltransferase activities. Moreover, NAT10 is closely associated with the pathogenesis of tumors, Hutchinson-Gilford progeria syndrome (HGPS), systemic lupus erythematosus, pulmonary fibrosis, depression and host-pathogen interactions. In recent years, mRNA acetylation has emerged as a prominent focus of research due to its pivotal role in regulating RNA stability and translation. NAT10 stands out as the sole identified modification enzyme responsible for RNA acetylation. There remains some ambiguity regarding the similarities and differences in NAT10's actions on protein and RNA substrates. While NAT10 involves acetylation modification in both cases, which is a crucial molecular mechanism in epigenetic regulation, there are significant disparities in the catalytic mechanisms, regulatory pathways, and biological processes involved. Therefore, this review aims to offer a comprehensive overview of NAT10 as a protein and RNA acetyltransferase, covering its basic catalytic features, biological functions, and roles in related diseases.

Keywords: Ac4C; Acetylation; NAT10; Remodelin; Tumor.

Fig. 1

NAT10 and Kre33 secondary structure and tertiary structure. A The Human NAT10 gene is located on chromosome 11 p13, consisting of 1025 amino acids, mainly composed of DUF1726, helicase, N-acetyltransferase, and tRNA binding four domains, in which the N-terminal and C-terminal contain NuLSs. B In yeast, NAT10, known as Kre33, is made up of 1056 amino acids and has the same four major domains as human cells, which are highly similar in structural domains to human NAT10 but with different start and stop positions in each domain. Respectively, Kre33 also contains an NLS at its N-terminus and a coiled-coil motif responsible for protein interactions at its C-terminus. Additionally, Kre33 contains TmcA-specific motifs: TS1, TS2 and TS3. 3D Structures were modeled with Alphafold (https://alphafold.com)

Fig. 2

Subcellular localization of NAT10. A. NAT10 predominantly localizes to the nucleolus in normal cells. Inhibition of GSK-3β by LiCl hampers NAT10 phosphorylation and ubiquitin–proteasome degradation pathways, leading to increased nuclear accumulation and enhanced nuclear output of NAT10. This phenomenon may contribute to its cytoplasmic and cell membrane accumulation, thereby promoting metastasis with colon cancer cells. B. The complete NuLS of NAT10 encompasses residues 68–75 and 989–1018, while the deletion of residues 989–1018 results in the translocation of NAT10 into the cytoplasm. Further deletion of residues 68–75 leads to the enrichment of NAT10 on the cell membrane. Deletion of NuLSs in NAT10 can facilitate α-tubulin acetylation, enhancing microtubule stability as well as stimulating actin remodeling for regulating cell movement and promoting liver cancer cell metastasis

Fig. 3

The role of NAT10 as a protein acetylase. Histone acetyl modification is regulated by the HAT and HDAC families, and NAT10 belongs to the GCN5-associated N-acetyltransferase family in the HAT family. hsSUN1 targets NAT10 to concentrate chromosomes, and NAT10 acetylates histones H2B and H4 to promote DNA depolymerization and chromosome concentration and separation during post-mitosis. Through non-histone acetylation modification, NAT10 affects its stability, subcellular localization, and protein–protein interaction, and participates in many mesobiological functions such as chromosome construction, DNA replication initiation, and gene expression regulation

Fig. 4

NAT10 interacts with co-factors to facilitate ac4C modification in tRNA, rRNA, and mRNA. The presence of the antisense sequence in snoRNA is essential for NAT10 to bind to the target sequence involved in the ac4C modification of 18 s rRNA. During tRNA ac4C modification, THUMPD1 associates with tRNA and assists NAT10 in catalyzing the formation of ac4C modification within the D-arm structure of tRNASer and tRNALeu. In mRNA, ac4C is predominantly localized within the CDS, significantly enhancing stability and translation efficiency. Conversely, ac4C present in the 3'UTR region exerts specific effects. However, ac4C located in the 5'UTR region inhibits translation through direct and indirect mechanisms, which are related to the position of ac4C in the 5'UTR. ac4C adjacent to the AUG initiation codon directly inhibits translation by disrupting the interaction between t6A modification in initiation methionine (tRNAiMet) and mRNA. In addition, ac4C downstream of upTIS (upstream translation initiation site) competitively inhibits aTIS (annotated translation initiation site) by enhancing the effect of upTIS. Thereby indirectly inhibiting translation

Fig. 5

NAT10 participates in cellular phenotypes as a protein acetyltransferase. NAT10 catalyzes the protein acetylation-mediated mechanisms of CCDC84, Eg5, H2B, H4, and α-tubulin, promoting cell division. NAT10 catalyzes the acetylation of α-tubulin, leading to a nuclear-cytoplasmic ratio imbalance and causing cell senescence. Similarly, NAT10 catalyzes the acetylation of PARP1, MORC2, and p53, affecting their molecular mechanisms to promote DNA damage repair. Additionally, NAT10 affects cell autophagy by catalyzing the acetylation of Che-1 and NAT10 self-acetylation

Fig. 6

NAT10 participates in cellular phenotypes as RNA acetyltransferase. NAT10 catalyzes the ac4c modification of mRNAs for CCND2, JUN, and ETV4 genes, which mediates related mechanisms and promotes cell proliferation. NAT10 also catalyzes the ac4c modification of mRNAs for VEGFA, OCT4, SOX2, and RUNX2, etc. genes, which promotes related pathways and affects cell differentiation. Furthermore, NAT10 modifies the ac4c modification of P16 mRNA, which changes the activity of the P16/CDK6/CCND1 signal axis and affects cell senescence