Composition and biological significance of the human Nalpha-terminal acetyltransferases

Abstract

Protein Nalpha-terminal acetylation is one of the most common protein modifications in eukaryotic cells, occurring on approximately 80% of soluble human proteins. An increasing number of studies links Nalpha-terminal acetylation to cell differentiation, cell cycle, cell survival, and cancer. Thus, Nalpha-terminal acetylation is an essential modification for normal cell function in humans. Still, little is known about the functional role of Nalpha-terminal acetylation. Recently, the three major human N-acetyltransferase complexes, hNatA, hNatB and hNatC, were identified and characterized. We here summarize the identified N-terminal acetyltransferase complexes in humans, and we review the biological studies on Nalpha-terminal acetylation in humans and other higher eukaryotes.

Figure 1

Composition of the four different hNatA complexes. The hNatA subunits hNaa10p, hNaa11p, hNaa15p and hNaa16p can combine to form four variants of the hNatA complex. All subunits tested bind to ribosomes (hNaa11p not tested yet), suggesting that all four variants can acetylate nascent polypeptides (e.g polypeptide with an N-terminal Serine) co-translationally. The gradient illustrates the expected abundance of the various complexes. Based on EST data and immunoprecipitation experiments [21], hNaa10p-hNaa15p forms the most abundant version of the complex, displaying a stochiometric relationship of 6:1 compared to the hNaa10p-hNaa16p complex in HEK293 cells. The hNaa11p-hNaa15p and hNaa11p-hNaa16p complexes are probably present to an even lesser extent in most tissues, except for tissues like testis, where hNaa11p is upregulated. In the lower part of the figure it is indicated which experimental data that forms the evidence of the complex formations. IP, immunoprecipitation; MS, Mass Spectrometry; WB, Western Blotting.

Figure 2

Knockdown of hNAA10 of the hNatA complex leads to apoptosis and cell cycle arrest. Knockdown of hNAA10 leads to reduced acetylation of hNaa10p subtrates [9]. As a direct or indirect effect of this, apoptosis and cell cycle arrest is observed [8]. Direct acetylation of β-catenin has been implicated in the cell cycle arrest mediated by hNAA10 knockdown [35]. Loss of acetylation can lead to reduced Cyclin D1 expression, and subsequent cell cycle arrest in the in the G₀-G₁ phase. One hypothetical mechanism is that hNatA affects cell cycle indirectly via a HAT (Histone Acetyltransferase), acting on β-catenin or directly or indirectly at the level of Cyclin D1 expression. This is more thoroughly issued in a previous publication [40]. More experimental studies are needed to determine the mechanisms through which hNatA knockdown phenotypes are formed.

Figure 3

Knockdown of hNAA20 of the hNatB complex leads to inhibition of growth and cell cycle arrest. Knockdown of hNAA20 may lead to reduced acetylation of hNaa20p substrates. As a direct or indirect effect of this, inhibition of cell growth, and G₀-G₁ cell cycle arrest is observed. The finding that p21 is upregulated after hNAA20 knockdown suggest a mechanism where loss of hNaa20p mediated acetylation leads to p21-mediated cell cycle arrest.

Figure 4

Knockdown of hNAA30 of the hNatC complex leads to p53-dependent apoptosis. Knockdown of hNAA30 may lead to the reduced acetylation of hNaa30p substrates. As a direct or indirect effect of this, p53 is stabilized and phosphorylated on Serine 37, and subsequently, transcription of p53 downstream proapoptotic genes NOXA, KILLER and FAS is activated, resulting in apoptosis.