Boster Pathways-> Epigenetics


Protein Acetylation Signaling Pathway


Protein acetylation is a reversible post-translational modification that is critical for protein function, chromatin structure, and gene expression.

an Overview of Protein Acetylation Signaling Pathway

Acetylation is a major post-translational modification of proteins in the cell, with numerous effects on both the protein and metabolome levels. The acetyl group, which is donated by the metabolite acetyl-coenzyme A, can be co- or post-translationally attached to the N-terminal -amino group of proteins or to the -amino group of lysine residues. Numerous N-terminal and lysine acetyltransferases catalyze these reactions. When lysine acetylation occurs, the reaction is reversible enzymatically via tightly controlled and metabolism-dependent mechanisms. The balance of acetylation and deacetylation is critical for a variety of critical cellular processes. Our understanding of protein acetylation has grown significantly in recent years as a result of global proteomics analyses and in-depth functional studies.

Bosterbio provides an overview of protein acetylation and the associated acetyltransferases, with a particular emphasis on how protein acetylation regulates metabolic processes and the physiological consequences associated with protein acetylation.

Histone acetylation

Histone H3 lysine 4 acetylation (H3K4ac) or H3K27me3 are frequently used to distinguish active enhancers from inactive enhancers and poised enhancers. This method of identification, however, does not distinguish completely between other types of enhancers, such as super-enhancers. H3K122ac has been found to be enriched with H3K27ac on the active enhancer. Although H3K122ac can be used to identify some novel enhancers, some of these novel enhancers will be enriched in H3K27ac as well. This property generates novel concepts for comprehensive identification enhancers. Acetylation of histones is also involved in the repair of DNA replication forks. The nucleosome acetyltransferase of H4 (NuA4) catalyzes the acetylation of H4 at four lysine residues at positions 5, 8, 12, and 16, a process known as N-acetylation. This modification alters the structure of chromatin, thereby facilitating the repair of DNA replication forks that have broken. By stabilizing the expression of NuA4, SWI1 promotes histone H4 acetylation. Without SWI1, the chromatin modification-related protein vid21, a regulatory subunit of NuA4, becomes unstable, resulting in a decrease in histone H4 acetylation. It is reported that the level of H3K56ac increases as cell density increases, and that H3K56ac levels also increased as lactic acid levels increased. This phenomenon may be explained by changes in SIRT6 levels. Additionally, the level of H3K56ac was increased in cells with low acetylation and decreased in cells with high acetylation immediately after DNA damage, indicating a link between acetylation and DNA repair.

Additionally, the histone acetyltransferase Gcn5p is a nuclear HAT catalytic subunit. Gcn5p catalyzes histone H3 and H4 acetylation at specific lysines, which results in N-acetylation of specific lysines in the amino-terminal domains, thereby promoting cell growth. These findings suggest that normal cell cycle progression requires acetylation of specific lysines at H3 and H4. Oridonin is a diterpenoid tetracycline that is a significant traditional Chinese herb. Oridonin has been shown to inhibit tumor cell proliferation and induce apoptosis, possibly by increasing histone H3 hyperacetylation.

Protein ACETYLATION

Additionally, non-histone proteins, such as p53, can be acetylated. Although non-histone protein acetylation has been studied for a shorter period of time than histone protein acetylation, non-histone protein acetylation has received increased attention recently due to its numerous regulatory functions. There are numerous non-histone proteins that can be acetylated, the most abundant of which are TFs. These non-histone proteins play a significant role in a variety of physiological processes, including gene transcription and protein folding.

In response to signaling pathways, acetylation complexes (such as CBP/p300 and PCAF) or deacetylation complexes (such as Sin3, NuRD, NcoR, and SMRT) are recruited to DNA-bound transcription factors (TFs). Hyperacetylation of histones by histone acetyltransferases (HATs) is associated with transcriptional activation, whereas deacetylation of histones by histone deacetylases (HDACs) is associated with transcriptional repression. Acetylation of histones stimulates transcription by remodeling higher order chromatin structure, weakening histone-DNA interactions, and providing binding sites for transcriptional activation complexes containing bromodomain-containing proteins that bind acetylated lysine. Histone deacetylation inhibits transcription by forming compact higher order chromatin and excluding bromodomain-containing transcription activation complexes. Hypoacetylation of histones is a characteristic of silent heterochromatin. A growing number of non-histone proteins have been shown to be acetylated at specific sites, which regulates their activity, localization, specific interactions, and stability/degradation.

Surprisingly, recent advances in mass spectrometry technologies have enabled high-resolution mapping of the majority of the proteome's acetylation sites. These studies established that the "acetylome" contains nearly 3600 acetylation sites in approximately 1750 proteins, implying that this modification is one of the most prevalent in nature. Indeed, it appears as though this mark has the ability to modulate the activity of proteins involved in a variety of biological processes, including chromatin remodeling, cell cycle, splicing, nuclear transport, mitochondrial biology, and actin nucleation. Acetylation is critical for immunity, circadian rhythmicity, and memory formation at the organismal level. Protein acetylation is becoming a more attractive target in the development of drugs for a variety of disease conditions.