N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae

Varland, Sylvia; Aksnes, Henriette; Kryuchkov, Fedor; Impens, Francis; Haver, Delphi Van; Jonckheere, Veronique; Ziegler, Mathias; Gevaert, Kris; Damme, Petra Van; Arnesen, Thomas

doi:10.1074/mcp.ra118.000982

Cited by 25 publications

(41 citation statements)

References 86 publications

(124 reference statements)

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“…NatB mediated Ntacetylation is efficient, and nearly all proteins that code as NatB substrates are indeed NatB substrates, which is not true for other Nt-acetyltransferases. Interestingly, yeast NatB substrates are predominantly, near 100%, found in the acetylated state [28,29]. In line with these observations, we showed that Nma1 and Nma2 peptides identified from WT cells were 100% acetylated whereas Nma1 or Nma2 peptides identified from NatB mutants were 95%-100% non-acetylated [21].…”

Section: Introductionsupporting

confidence: 84%

“…Nt-acetylation of Nma1 and Nma2 is likely important for mediating transient interactions or complex formation with proteins that either help protein folding or block key residues from being targeted by protein degradation machinery. This may help answer an interesting observation that in a normal cell Nma1, Nma2 and most other NatB substrates are always Nt-acetylated [21,29]. It is likely that non-acetylated populations of these proteins exist but are hard to identify because they are degraded before reaching maturity.…”

Section: Discussionmentioning

confidence: 96%

“…Potential NatA substrates include 25% of proteins vs 15% for NatB, possibly indicating NatA has a larger workload [51]. Additionally, most potential NatB substrates are indeed NatB substrates and are acetylated to near 100% efficiency, whereas NatA does not acetylate all of its potential substrates, and the level of acetylation on a NatA-specific substrate can also be different [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…Based on reported proteomic data we chose to insert Ser between the first two amino acids, Met and Asp, in Nma1 and Nma2 (Nma1/2 MD à Nma1/2 MSD ) ( Fig. 2A, right panel) because this peptide sequence is almost always acetylated by NatA [28,29].…”

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

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N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

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ABSTRACTNAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are not completely understood. We previously identified the N-terminal (Nt) protein acetyltransferase complex NatB as a NAD+ homeostasis factor. Cells lacking NatB show an approximate 50% reduction in the NAD+ level and aberrant metabolism of NAD+ precursors, which are associated with a decrease of nicotinamide mononucleotide adenylyltransferases (Nmnat) protein levels. Here we show this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins, and not other NatB substrates. Nt-acetylation is a critical regulator of protein degradation by the N-end rule pathways, indicating absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats does not significantly differ from Nt-acetylated Nmnats, suggesting reduced Nmnat levels in NmatB mutants are not due to increased post-translational degradation of non-Nt-acetylated Nmnats. In line with these observations, deletion or depletion of N-rule pathway ubiquitin E3 ligases in NatB mutants is not sufficient to restore NAD+ levels. Moreover, the status of Nt-acetylation does not alter the rate of translation initiation of Nmnats. Collectively our studies suggest absence of Nt-acetylation may increase co-translational degradation of nascent Nmnat polypeptides, which results in reduced Nmnat levels in NatB mutants. Nmnat activities are essential for all routes of NAD+ biosynthesis. Understanding the regulation of Nmnat protein homeostasis will facilitate our understanding of the molecular basis and regulation of NAD+ metabolism.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

See 2 more Smart Citations

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…upon growth in glucose rich media. A recent study confirmed changed Nt-acetylation levels of Nat substrates in a protein-specific and not global manner under growth conditions conferring low acetyl-CoA levels (Varland et al, 2018). Overall, the selective effect on fewer protein targets (as compared to NatB) qualifies NatA to play a regulatory role in specific cell responses.…”

Section: Global Protein Aggregation Upon Lack Of Nt-acetylationmentioning

confidence: 88%

N^α-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles inSaccharomyces cerevisiae

Friedrich

Zedan

Heßling

et al. 2019

Preprint

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N-terminal (Nt)-acetylation is a highly prevalent co-translational protein modification in eukaryotes, catalyzed by at least five Nt-acetyltransferases (Nat) with differing specificities. Nt-acetylation has been implicated in protein quality control but its broad biological significance remains elusive. We investigated the roles of the two major Nats of S. cerevisiae, NatA and NatB, by performing transcriptome, translatome and proteome profiling of natAΔ and natBΔ mutants. Our results do not support a general role of Nt-acetylation in protein degradation but reveal an unexpected range of Natspecific phenotypes. NatA is implicated in systemic adaptation control, as natAΔ mutants display altered expression of transposons, sub-telomeric genes, pheromone response genes and nuclear genes encoding mitochondrial ribosomal proteins. NatB predominantly affects protein folding, as natBΔ mutants accumulate protein aggregates, induce stress responses and display reduced fitness in absence of the ribosome-associated chaperone Ssb. These phenotypic differences indicate that controlling Nat activities may serve to elicit distinct cellular responses.

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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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N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae

Cited by 25 publications

References 86 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N^α-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles inSaccharomyces cerevisiae

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

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N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae

Cited by 25 publications

References 86 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

Nα-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles inSaccharomyces cerevisiae

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

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N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N^α-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles inSaccharomyces cerevisiae