Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis
Abstract
:1. Post-Translational Modifications in Proteins
2. PTMs in the Generation of Autoimmunity
3. PTMs in Inflammatory Immune-Mediated Rheumatic Diseases
4. AMPAs in the Pathogenesis, Diagnosis and Prognosis of RA
5. Synthetic Post-Translationally Modified Peptides for the Specific Detection of Autoantibodies in RA Patients
Protein | Sequence | PTM Peptide | References |
---|---|---|---|
Filaggrin | (306–324) (304–324) | SHQESTCitGRSRGRSGRSGS (cyclic) HQCESTCitGRSRGRCGRSGS (cyclic) HQCHQESTCitGRSRGRCGRSGS (cyclic) HSGIGHGQASSAVRDSGHCitGYS HSTSQEGQDTIHGHCitGS | [81,93] [94,95,96,97,98] [81,91,99] [55] [55] |
Profilaggrin | (293–310) | TIHAHPGSCitCitGGRHGYHH TIHAHPGSCitRGGCitHGYHH | [100] |
Fibrinogen (α-chain) | (27–43) (31–50) (36–50) (41–60) (84–96) (211–230) (556–575) (563–583) (580–600) (616–636) (617–631) (621–635) | FLAEGGGVCitGPRVVERH GGGVCitGPRVVERHQSACKDS GPCitVVECitHQSASKDS ECitHQSACKDSDWPFCSDEDW (cyclic) TSSTSYNCitGDSTF DLLPSCitDRQHLPLIKMKPVP (cyclic) NTKESSSHHPGIAEFPSCitGK (cyclic) HHPGIAEFPSCitGKSSSYSKQF SKQFTSSTSYNCitGDSTFESKS THSTKCitGHAKSCitPVCitDCDDVL (cyclic) HSTKRGHAKSRPVCitG CitGHAKSCitPVCitGIHTS | [56,95] [100] [86,91,93,94,98,101] [102] [95] [102] [97,102] [91,93,94,96,98,103] [91,93,94,98,103] [100,102] [83] [86,91,93,94,96,98,101] |
Fibrinogen (β-chain) | (36–52) (43–62) (60–74) (54–80) (62–81) (62–81) | NEEGFFSACitGHRPLDKK ARGHCitPLDKKREEAPSLCitPA CitPAPPPISGGGYCitACit EEAPSLCitPAPPPISGGGYCitACitPAKAAA APPPISGGGYCitARPAKAAAT APPPISGGGYRACitPAKAAAT | [56,91,93,94,96,97,98] [83] [86,91,93,94,96,98,101] [95] [94,96,97,103] [94,96,97,103] |
Fibronectin | (1029–1042) (2350–2362) | LTVGLTCitCitGQPRQY YNQYSQCitYHQRTN | [95] [95] |
Vimentin | (2–17) (47–72) (59–70) (60–75) (265–278) (420–435) | STCitSVSSSSYCitCitMFGG STSRSLYASSPGGVYATRSSAVRLCitS GRVYATCitSSAVR VYATRSSAVRLCitSSVP LTAALCitDVCitQQYES SLNLCitETNLDSLPLVD | [56,93,94,96,97,98] [84] [104,105] [56,93,94,96,97,98] [95] [95] |
α-enolase | (5–21) | CKIHACitEIFDSCitGNPTVEC (cyclic) | [56,85,91,93,94,95,96,97,98] |
Collagen type II Collagen type II (citC1III) | (282–298) (359–369) | GLPGVKGHCitGYPGLDGA (GPO)5-GACitGLTGCitPGDA(GPO)2-GKKYG | [95] [91,96,97,98] |
Biglycan | (247–266) | EDLLCitYSKLYCitLGLGHNQIR (cyclic) | [90,102] |
Clusterin | (221–240) (334–353) | PKSCitIVCitSLMPFSPYEPLNF (cyclic) AECitLTCitKYNELLKSYQWKML | [90,102] [100] |
β-actin | (191–216) | MKILTECitGYSFTTAECitEIVCitDIKEKL | [95] |
MNDA | (121–135) | KLTSEACitGCitIPVAQK | [95] |
Histone 2A Histone 2B | (1–20) (62–81) | MSGCitGKTGGKACitAKAKSCitSS (cyclic) IMNSFVNDIFECitIAGEASCitL (cyclic) | [90,102] [90,102] |
Histone 4 | (33–47) | AIRRLACitCitGGVLRIS | [62] |
Tenascin C | (2176–2200) | EHSIQFAEMKLCitPSNFCitNLEGCitCitKR | [106] |
6. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Human Disease | Target Proteins | PTM | References |
---|---|---|---|
Multiple Sclerosis | Myelin proteins (MBP), GFAP, Histone H3 | Citrullination | [9] |
Rheumatoid Arthritis Palindromic Rheumatism | Proteins of inflamed joints and synovium: Collagen type II, Fibrinogen, Fibrin, Vimentin, α-Enolase | Citrullination Carbamylation Acetylation Glycosylation | [10,11,12,13] |
Type 1 Diabetes | Proteins modified in beta-cells and neutrophils (IAPP, IA-2, IGRP, GAD65, GRP78) | Citrullination | [14] |
Systemic Lupus Erythematosus | Intracellular macromolecules: ribonucleoproteins and nucleosomes (U1-70K, Ro/SSA, La/SSB, SmD1, H2B, H4, …) | Phosphorylation Glycosylation Acetylation Iso-aspartylation Methylation Ubiquitination | [15,16,17] |
Celiac disease | Adherence and tight junction proteins; transcription factor (PPARγ); serum IgG and IgA1 Wheat gliadin | Phosphorylation Ubiquitination Glycosylation Citrullination | [18,19] |
Psoriasis/Psoriatic arthritis | Keratin; Cathelicidin LL37 | Citrullination Carbamylation | [20,21] |
Antiphospholipid Syndrome | Apolipoprotein (β2GPI), Vimentin | Oxidation/ Sialylation Citrullination | [22] |
Primary Biliary Cirrhosis | PDC-E2 | Acylation/ oxidation | [23] |
Inflammatory Bowel Disease | Kinases: MAPKs and PKB/Akt; DNA-binding transcription factor; NF-κB; Histone H3 | Phosphorylation Ubiquitination Glycosylation Citrullination | [19,24] |
Sjogren’s Syndrome | α-Enolase | Citrullination | [25] |
Protein | PTM | Peptide Sequence | References |
---|---|---|---|
Filaggrin | Homocitrulline Acetyl-Lysine | HQCHQESThCitGRSRGRCGRSGS HQCHQESTKAcGRSRGRCGRSGS | [99] |
Vimentin | Homocitrulline Acetyl-Lysine Acetyl-ornithine | GRVYAThCitSSAVR GRVYATKAcSSAVR GRVYATOrAcSSAVR | [93,104,105,108,109] |
Vimentin | Homocitrulline Acetyl-Lysine | VYAThCitSSAVhCitLhCitSSVP VYATKAcSSAVKAcLKAcSSVP | [99] |
Fibrinogen α | Homocitrulline Acetyl-Lysine | FLAEGGGVhCitGPRVVERH FLAEGGGVKAcGPRVVERH | [99] |
Fibrinogen β | Homocitrulline | ARGHRPLDKhCitREEA | [93,109] |
Fibrinogen β | Homocitrulline | AKAAATQhCitKVER (cyclic) | [93,109] |
Fibrinogen β | Homocitrulline Acetyl-Lysine | NEEGFFSAhCitGHRPLDKK NEEGFFSAKAcGHRPLDKK | [99] |
Fibrinogen γ | Carbamylation | QKIVNLKEKVAQLEAQCQEPCKDTVQI * WMNKCHAGHLNGVYYQGGTYSKASTPN * | [110] |
Enolase | Homocitrulline Homocitrulline Acetyl-Lysine | KIHAhCitEIFDShCitGNPTVE (cyclic) KIHAhCitEIFDShCitGNPTV (linear) KIHAKAcEIFDSKAcGNPTV (linear) | [93,111] [99] |
Histone 2B | Acetyl-Lysine | SAPAPKKAcGSKKAVTKAQ (cyclic) | [93,112] |
Histone 4 | Acetyl-Lysine Acetyl-Lysine Acetyl-Lysine | SGRGKAcGGKAcGLGKAcGGAKAcRH SGRGKAcGGKGLGKGGAKRH SGRGKGGKGLGKGGAKAcRH | [93,112] |
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Haro, I.; Sanmartí, R.; Gómara, M.J. Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis. Int. J. Mol. Sci. 2022, 23, 15803. https://doi.org/10.3390/ijms232415803
Haro I, Sanmartí R, Gómara MJ. Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis. International Journal of Molecular Sciences. 2022; 23(24):15803. https://doi.org/10.3390/ijms232415803
Chicago/Turabian StyleHaro, Isabel, Raimon Sanmartí, and María J. Gómara. 2022. "Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis" International Journal of Molecular Sciences 23, no. 24: 15803. https://doi.org/10.3390/ijms232415803