NAA80 is actin’s N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility

Drazic, Adrian; Aksnes, Henriette; Marie, Michaël; Boczkowska, Małgorzata; Varland, Sylvia; Timmerman, Evy; Foyn, Håvard; Glomnes, Nina; Rębowski, Grzegorz; Impens, Francis; Gevaert, Kris; Domínguez, Roberto; Arnesen, Thomas

doi:10.1073/pnas.1718336115

Cited by 167 publications

(243 citation statements)

References 37 publications

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“…Surprisingly, the cells lacking NAA80, migrates faster than the control cells as demonstrated by cell culture scratch wound assay and chemotaxis migration [6]. We here further present single-cell analyses demonstrating at least a doubled speed for the random cellular movement (Figure 1).…”

Section: Naa80 Acts Like a Brake To Keep Cell Migration In Checksupporting

confidence: 57%

“…Posttranslational activity is also suggested for the other more recently identified NATs, NAA60/NatF and NAA70/NatG due to their subcellular localization [8,9]. Contrary to the typical NAT, NAA80/NatH appears to be highly selective with actin as the only substrate in vivo in animals, as demonstrated by the lack of actin Nt-acetylation in NAA80 KO cells by COFRADIC analysis [6]. There are at least two factors underlying this narrow substrate specificity.…”

Section: Naa80 Acetylates Actin’s N-terminusmentioning

confidence: 97%

“…Through an N-terminal-specialized mass spectrometry analysis called COFRADIC, a previously predicted NAT of unknown substrate specificity (NAT6/FUS2), was identified not only as a true NAT, but as a NAT with specificity for actin [6]. This NAT was thus named NAA80/NatH according to the NAT nomenclature [7] and joins the previously described NAT family (NatA-G) of which most function cotranslationally towards an array of substrates, thus combined covering the majority of the proteome.…”

Section: Naa80 Acetylates Actin’s N-terminusmentioning

confidence: 99%

“…One can thus say that NAA80, by acetylating actin’s N-terminus, acts as a natural brake in the cells in order to ensure normal migration speed. Under the microscope, the NAA80 knockout cells also revealed structural changes in the actin cytoskeleton that matched increased migration speed [6]. …”

Section: Naa80 Acts Like a Brake To Keep Cell Migration In Checkmentioning

confidence: 99%

“…To date, there is little knowledge on the biological function of actin Nt-acetylation, mainly due to the lacking identification of the actin-specific enzyme. Recent work, however, identified NAA80 as actin’s NAT, and revealed the cellular functions it exerts through alterations of actin’s biochemical properties [6]. …”

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confidence: 99%

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Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin

Aksnes

Marie

Arnesen

et al. 2018

Communicative & Integrative Biology

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Actin is the most abundant protein in our cells, and also one of the most studied. Nevertheless, an important modifier of actin, the N-terminal acetyltransferase (NAT) for actin, remained unknown until now. The recent identification of the enzyme that catalyzes actin acetylation, has opened up for functional studies of unacetylated actin using knockout cells. This enzyme, called NAA80 (Nα-acetyltransferase 80) or NatH, belongs to the NAT family of enzymes, which together provides N-terminal acetylation for around 80 % of the human proteome. In many cases, N-terminal acetylation is essential. In the case of actin, the acetyl group that NAA80 attaches to actin plays an important role in actin’s polymerization properties as well as in actin’s function in cell migration.

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Section: Naa80 Acts Like a Brake To Keep Cell Migration In Checksupporting

confidence: 57%

Section: Naa80 Acetylates Actin’s N-terminusmentioning

confidence: 97%

Section: Naa80 Acetylates Actin’s N-terminusmentioning

confidence: 99%

Section: Naa80 Acts Like a Brake To Keep Cell Migration In Checkmentioning

confidence: 99%

mentioning

confidence: 99%

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Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin

Aksnes

Marie

Arnesen

et al. 2018

Communicative & Integrative Biology

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A nonsense variant in the N‐terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft

Varland

Brønstad

Skinner

et al. 2023

American J of Med Genetics Pt A

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Most human proteins are N‐terminally acetylated by N‐terminal acetyltransferases (NATs), which play crucial roles in many cellular functions. The NatC complex, comprising the catalytic subunit NAA30 and the auxiliary subunits NAA35 and NAA38, is estimated to acetylate up to 20% of the human proteome in a co‐translational manner. Several NAT enzymes have been linked to rare genetic diseases, causing developmental delay, intellectual disability, and heart disease. Here, we report a de novo heterozygous NAA30 nonsense variant c.244C>T (p.Q82*) (NM_001011713.2), which was identified by whole exome sequencing in a 5‐year‐old boy presenting with global development delay, autism spectrum disorder, hypotonia, tracheal cleft, and recurrent respiratory infections. Biochemical studies were performed to assess the functional impact of the premature stop codon on NAA30's catalytic activity. We find that NAA30‐Q82* completely disrupts the N‐terminal acetyltransferase activity toward a classical NatC substrate using an in vitro acetylation assay. This finding corresponds with structural modeling showing that the truncated NAA30 variant lacks the entire GNAT domain, which is required for catalytic activity. This study suggests that defective NatC‐mediated N‐terminal acetylation can cause disease, thus expanding the spectrum of NAT variants linked to genetic disease.

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Posttranscriptional and Posttranslational Regulation of Actin

Rodríguez

Kashina

2018

The Anatomical Record

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Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle β-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin’s essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin’s nucleotide-level regulation.

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NAA80 is actin’s N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility

Cited by 167 publications

References 37 publications

Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin

Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin

A nonsense variant in the N‐terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft

Posttranscriptional and Posttranslational Regulation of Actin

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