Study On Post-translational Modification Of Lysine 2-hydroxyisobutyrylation In Psoriasis

Objective: Lysine 2-hydroxyisobutyrylation is a newly discovered post-translational modification.It has been found to occur in a wide variety of organisms and to participate in some important metabolic processes.Although this modification is an important type of protein acylation,its role in psoriasis remains unstudied.We quantified and compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients to explore the role of lysine 2-hydroxyisobutyrylation in psoriasis.Methods: Lesional and nonlesional psoriasis skin samples were taken from 45 psoriasis patients.Skin tissue samples were randomly divided into three groups.Experiments were then performed in three sets of samples for repeated trials.Skin samples were explored with an integrated approach involving tandem mass tag labeling,high performance liquid chromatography fractionation,lysine 2-hydroxyisobutyrylation antibody affinity enrichment,and LC-MS/MS.Modified sites in protein groups were identified and quantified.And the difference between lesional and nonlesional psoriasis skin were then analyzed.The identified loci were compared with the psoriasis susceptibility loci found so far.Gene Ontology proteome annotation was performed,and the proteins were classified into three categories: the biological process,cellular component and molecular function categories.The Kyoto Encyclopedia of Genes and Genomes database was used to identify enriched pathways.Soft motif-x was used to analyze patterns of sequences with amino acids in specific positions for all protein sequences.Bioinformatics differences for lesional and nonlesional psoriasis skin samples were also compared.Results: Lysine 2-hydroxyisobutyrylation was found in large quantities in both normal and diseased dermal tissues.However,there were a number of clear and significant differences between normal and diseased skin tissue.By comparing,lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin.In particular,the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9(ratio?=?0.140,p-value?=?0.000371),while the most upregulated site was found in TNC(ratio?=?3.082,p-value?=?0.0307).Loci associated with psoriasis,including FUBP1,SERPINB2 and S100A9,also exhibited significant regulation.Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins.And bioinformatics analysis suggested that a variety of proteins involved in cellular components,molecular functions and biological processes are differentially modified in skin lesions.The PI3K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin.Conclusion: Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin.However,there were a number of clear and significant differences between normal and diseased skin tissue.Many proteins and some other important pathways were significantly regulated at the modification level in diseased tissue,and many of the altered proteins were clearly associated with psoriasis.Among them,S100A9 and TNC were most significantly modified,and the PI3K-Akt signaling pathway was up-regulated.Future exploration of protein modifications will help us understand psoriasis more thoroughly.We hope that this research will provide new insights into psoriasis.