Correlation Between Protein Lysine Acetylation Modification And Pathogenesis Of Psoriasis

Background Psoriasis is a chronic inflammatory skin disease characterized by erythema and scales.This disease is easy to relapse and difficult to cure,which is often associated with other systemic diseases such as cancer and autoimmunity disease.The prevalence of psoriasis in the Chinese population has reached 0.47%,and there has been an upward trend in recent years.However,the pathogenesis of psoriasis has not been known so far,and it is considered to be a complex disease.Genome-wide approaches have identified more than 60 psoriasis-susceptibility loci,but genes are estimated to explain only one-third of the heritability in psoriasis.The psoriasis phenotypes of monozygotic twins(with the same genotype)are inconsistent,suggesting that in addition to genetic predisposition factors,other epigenetic factors such as the environment also play a role.Epigenetics regulates gene expression from three levels: DNA methylation,non-coding RNA regulation,and histone modification.They are affected by environmental exposure,lifestyle,and age.Epigenetic modifications trigger different genetic loci and signaling pathways in different ethnic groups and are associated with a variety of inflammatory diseases.Protein modification is one of the basic mechanisms of epigenetic regulation.The regulation of genetic information at the chromatin level plays an important role in the determination of gene expression and cell fate.In recent years,a number of new protein modifications have been found,one of these modifications is lysine acylation,which includes acetylation(AC),propionylation(PR),butyrylation(BU),and croton acylation(CR).Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation through the modification of histones and nuclear transcription factors,but the research of protein lysine acetylation in psoriasis is much less.Objectives We used high-resolution liquid chromatography tandem mass spectrometry to quantify lysine acetylated proteomics in 45 lesional and non-lesional skins of patients with psoriasis,revealing profile of protein lysine acetylation and exploring effect of protein lysine acetylation on the level of posttranslational modification in psoriasis.Methods We collected lesional and non-lesional skin tissues from 45 patients with psoriasis vulgaris.After grinding the digested tissue,protein was extracted via using antibody to affine and enrich polypeptide.In this study,a quantitative ratio of Kac loci(PP/PN)> 1.2 was considered upregulation whereas a quantitative ratio < 0.83 was considered downregulation.We screen out statistically significant Kac loci for bioinformatics analysis and link with existing proteomics and psoriasis susceptibility genes to speculate the role of protein lysine acetylation modification and further complement the explanation of psoriasis.Results We used LC-MS/MS to quantify 685 Kac loci in 462 proteins of 45 patients with psoriasis vulgaris.The acetylome profiles displayed that 56 downregulated Kac loci in 53 proteins and only 5 upregulated Kac loci in 5 proteins.The most significant difference was found in the downregulation of Kac locus Lys318 in protein PSAT1(ratio = 0.56,P = 0.0001)and the upregulation of Kac locus Lys102 in protein PI3(ratio = 5.89,P = 0.0057).Comparing with the proteomic data,13(22.8%)differentially expressed proteins had significant differences of Kac loci,including DCN,MFAP4,SPTAN1,COL6A1,FLNA,SOD1,CAV1,CMA1,VCL,RPL11,RPL28,COL6A3,S100A9.We detected Kac loci in reported psoriasis susceptibility genes of Chinese population and found that the differences of Kac loci in 4 genes(GAPDH(12p13.31),S100A9(1q21.3),CLIC1(6p21.33)and VCL(10q22.2)),indicating that there was a correlation between gene variants and Kac modification.Bioinformatics analysis showed that most of proteins with downregulated Kac loci were associated with energy metabolism processes or pathways,suggesting that downregulated Kac modification might be involved in the pathogenesis of psoriasis via regulating energy metabolism.Conclusions In this study,56 downregulated Kac sites in 53 proteins and 5 upregulated Kac sites in 5 proteins were identified for psoriasis.Combined with proteomics data,a total of 13 proteins(22.8%)showed significant differences in Kac locus expression.In the psoriasis susceptibility locus,we detected that the expression products of the four genes have different Kac levels.In total,we established the first protein lysine acetylation map for psoriasis,and the results suggest that Kac modification in protein level may be involved in the pathogenesis of psoriasis.