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Review
. 2019 Jan 23:9:15.
doi: 10.3389/fonc.2019.00015. eCollection 2019.

Progression on Citrullination of Proteins in Gastrointestinal Cancers

Shuzheng Song  1 , Yingyan Yu  1
Affiliations
Review

Progression on Citrullination of Proteins in Gastrointestinal Cancers

Shuzheng Song et al. Front Oncol. .

Abstract

The citrullination modification (Cit) of proteins has received increasing attention in recent years. This kind of protein modification was first discovered in autoimmune diseases such as rheumatoid arthritis. The citrullination modification process is catalyzed by the peptidyl arginine deiminases (PADIs) family. A well-known citrullination of histone involves the key mechanism of neutrophil extracellular traps (NETs) of inflammation in the peripheral blood. Further studies revealed that citrullination modification of proteins also involves in carcinogenesis in human being. Citrullinated proteins disturbed the stability of proteins and caused DNA damages. There is increasing evidence that citrullinated proteins can be used as potential targets for cancer diagnosis or treatment. This review introduces the concept of citrullination modification of proteins, substrate proteins, examining methods and biological significances.

Keywords: PADIs; citrullination; histone; molecular targets; proteins.

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Figures

Figure 1
Figure 1
The chemical conversion process of protein citrullination. In the presence of calcium ions, PADIs could catalyze the formation of peptidyl citrulline from peptidyl arginine, which removes an amino group, accompanied by the positive charge becoming electrically neutral.
Figure 2
Figure 2
The chromosome location and structural characteristics of PADIs family. Five PADIs genes (PADI 1, 2, 3, 4, and 6) are located in the p36.13 of chromosome 1 across a region of approximately 500 k bases. PADIs members have similar structural regions, which can be divided into three sections: nitrogen zone, middle zone, and carbon end catalytic zone. Only PADI4 contains a nuclear localization signal at the nitrogen end of sequence, implying that PADI4 may play a role in the cell nucleus.
Figure 3
Figure 3
The schematic presentation of citrullinated modification of proteins and its biological significance. PADIs enzymes are activated through receptors of ER/EGFR/HER2, oxidative stress, hypoxia, and other microenvironment factors, which initiate autophagy and DNA damage. Increased PADIs catalyze citrullination modification of histones and non-histone proteins, and result in cell proliferation, epithelial-mesenchymal transition, migration, and inflammation. Citrullinated proteins as a new antigen may activate immune response of T cells or induce specific antibodies.
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