PADI4

Official Full Name

peptidyl arginine deiminase 4

Organism

Homo sapiens

GeneID

23569

Background

This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine residues to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. [provided by RefSeq, Jul 2008]

Synonyms

PAD; PAD4; PDI4; PDI5; PADI5;

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Detailed Information

Epigenetically suppression of p21 transcription and cell apoptosis inhibition of fibroblast-like synoviocytes from rheumatoid arthritis patients by PADI4

As a chronic autoimmune disease, rheumatoid arthritis (RA), characterized by chronic joint inflammation and cartilage erosion, has relation to genetic and environmental factors, such as viral infection, hormone levels and mental state. The underlying mechanism of 2-3 times higher morbidity of RA in women than in man remains unknown. In recent studies, apoptosis and proliferation of fibroblast-like synoviocytes (FLSs) played important role in the occurrence and development of RA has been confirmed. In the presence of Ca²⁺, peptidyl arginine can be converted into citrulline by peptidyl arginine deiminase (PAD), a process also known as citrullination. Among the five PAD family derived distinct isozymes, PADI1, PADI2, PADI3, PADI4 and PADI6, PADI4 is well expressed in a variety of blood cells. More than this, overexpression of PADI4 in synovial organization and peripheral blood mononuclear cells (PBMCs) has been observed in RA patients.

Citrullination of proteins caused changes in biological activity further role in the regulation of cell proliferation and apoptosis. Histones H3 and H4 were confirmed to be citrullinated by PADI4 at different Arginine residues. And arginine 3 residue of histone H4 (H4R3cit) and arginine 17 residue of histone H3 (H3R17cit) citrullination can be increased by PADI4 particularly. Non-histone protein vimentin was a recently identified direct substrate, which can be citrullinated by PADI4. Proliferation of FLSs isolated from RA patients can be effectively promoted by the citrullinated vimentin. Based on the fact that histone works as the major citrullination substrate of PADI4, there is a speculation of PADI4 playing a role in RA via the citrullination regulation on histone.

Counteraction of histone arginine methylation repression by PADI4, to be a coactivator of Tal1

As a critical activator or repressor of gene expression in hematopoiesis and leukemia, the transcription factor Tal1, whose mechanism of differential influences on the transcription of distinct genes has not been fully understood. In Stephan's research, PADI4 was demonstrated to be able to influence H3R2me2a as an epigenetic coactivator, and PRMT6 triggered H3R2me2a mark repression can be counteracted by PADI4 for active H3K4me3 mark augment and IL6ST expression increase at the Tal1/PADI4 target gene IL6ST site. So, there is a proposition that PADI4 influence on IL6ST transcription contributes to IL6ST expression control during lineage differentiation of hematopoietic stem/progenitor cells.

PADI4 Figure 1. Anti-apoptotic role of PADI4 in RA development. (Lieying Fan, et al. 2017)

References:

Fan L, Zong M, Gong R, et al. PADI4 epigenetically suppresses p21 transcription and inhibits cell apoptosis in fibroblast-like synoviocytes from rheumatoid arthritis patients. International journal of biological sciences, 2017, 13(3): 358.
Kolodziej S, Kuvardina O N, Oellerich T, et al. PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation. Nature communications, 2014, 5(1): 1-12.

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