TAp63, a Novel Protein Drug Target for Rheumatoid Arthritis

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint deterioration. Clinical outcomes in patients with active RA can be improved with the use of antirheumatic drugs such as methotrexate (MTX). Many patients rely on MTX to limit the devastating joint damage and functional disability typical of RA. Although the drug is a folate antagonist, its exact mechanism in patients with rheumatoid arthritis is largely unknown.

 

Previous research has shown that MTX also affects a type of white blood cell called CD4+ T cells. These cells are thought to play a role in the development of Ra-specificity, a balance between interleukin 17 production of helper T cells (Th17) and activation of CD4+ regulatory T cells (Treg). The researchers suspect that MTX affects CD4+ T cells by suppressing T cell activity and increasing Treg cells, but its specific role, except for folate metabolism, is unclear.

 

Recently, a group of researchers found that MTX targets the tumor protein p63 (TP63) in CD4+ T cells. Their findings were published online May 22, 2023 in the journal JCI Insight. The team was led by Dr. Akiro Suto, associate professor at the Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine and Chiba University Advanced Academic Research Institute.

 

They also included Dr. Kensuke Suga, Dr. Shigeru Tanaka and Dr. Hiroshi Nakajima from the Department of Allergy and Clinical Immunology at Chiba University, and Dr. Osamu Ohara from the Department of Applied Genomics at the Kazusa DNA Institute.

 

“We were keen to analyze gene expression before and after MTX treatment, as the drug likely targets CD4+ T cells and little is known about its effect on gene expression in patients with active RA,” explained Dr. Suto, discussing the team’s motivation for the study road.

 

The researchers used DNA microarray analysis of human CD4+ T cells from RA patients to understand how MTX affects gene expression. They also used gene knockdown, a molecular technique that suppresses a gene of interest, and RNA sequencing (RNA-seq) to verify gene function. The researchers found that TAp63, a protein isoform of TP63, is highly expressed in human and mouse Th17 cells.

 

Dr. Suto said: “TAp63 messenger RNA expression was significantly reduced in CD4+ T cells of patients treated with MTX. MTX also suppressed TAp63 protein in human and mouse Th17 cells. Inhibition of TAp63 in mouse Th17 cells leads to amelioration of autoimmune arthritis in mice. “

 

RNA-Seq and gene knockdown data revealed that another gene, FOXP3, a master regulator of Treg cells, is a target of TAp63. When TAp63 was “knocked out” in Treg cells, Foxp3 protein expression increased. Using reporter experiments, the researchers confirmed that TAp63 binds to the FOXP3 enhancer and represses it. Taken together, these findings suggest that TAp63 is intricately linked to the balance of Th17 and Treg cell differentiation. Thus, inhibition of TAp63 enhances the suppressive function of Treg cells, limiting autoimmune RA.

 

These findings reveal a powerful mechanism of MTX action and show how Treg cells are preserved in RA. They also demonstrate the potential of TAp63 as a new therapeutic target for RA.

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