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NHRI researchers find DUSP22 deficiency and UBR2 upregulation are keys to the induction of autoimmune diseases

  • Date: 2024-03-11
  • Update: 2024-03-12
  • Source: 國家衛生研究院
  • Views: 214

NHRI researchers find DUSP22 deficiency and UBR2 upregulation
are keys to the induction of autoimmune diseases

 

March 11, 2024

Scientists with Taiwan’s National Health Research Institutes (NHRI) have discovered that DUSP22 deficiency and UBR2 upregulation are keys to the pathogenesis of autoimmune diseases. Their findings were recently published in the prestigious international journal Nature Communications.

Autoimmune disease is the third most common catastrophic illness in Taiwan. In autoimmune diseases, one’s immune system mistakenly attacks one’s own healthy cells or organs. Patients with autoimmune diseases such as systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and rheumatoid arthritis need to receive treatments throughout their lives. Symptom alleviation for autoimmune disease is a long-standing challenge in the medical field. Understanding the disease pathogeneses will help development of novel therapies for autoimmune diseases.

After six years of indefatigable research, distinguished investigator Dr. Tse-Hua Tan and associate investigator Dr. Huai-Chia Chuang, both with NHRI’s Immunology Research Center, recently discovered that a key phosphatase, DUSP22, and an important E3 ubiquitin ligase, UBR2, control the induction of autoimmune diseases. They found that DUSP22 deficiency and UBR2 overexpression in T cells induce the activation of the T-cell kinase Lck and production of proinflammatory cytokines, leading to autoimmune diseases. Their work was published in the January issue of Nature Communications.

Since 2009, Dr. Tan’s research team has studied pathogenic mechanisms and precision medicine for SLE using genetically modified mice and human patient samples. In a 2014 Nature Communications paper, Dr. Tan’s research team demonstrated that the phosphatase DUSP22 is a key suppressor for Lck activation and T-cell-mediated autoimmune responses. The team collaborated with Drs. Yi-Ming Chen and Ming-Han Chen: physician scientists from Taipei Veterans General Hospital and Taichung Veterans General Hospital, respectively. In 2016 and 2023, they reported that DUSP22 amounts are lower than normal in peripheral blood T cells of SLE and AS patients. They found that DUSP22 downregulation in T cells of SLE patients contributes to overproduction of the proinflammatory cytokines IL-17, IFN-γ, and TNF-α, which then induce autoimmune diseases (such as SLE nephritis).

Dr. Tan’s research team further studied the role of DUSP22 in regulating T-cell activation by mass spectrometry-based analysis, single-cell RNA sequencing (scRNA-seq), gene knockout mice, and various biochemical experiments. Surprisingly, they found a novel mechanism for activating the T-cell kinase Lck. The DUSP22-interacting protein UBR2 (a ubiquitinating enzyme) ubiquitinates the T-cell kinase Lck, resulting in Lck activation and subsequent T-cell activation. They demonstrated that DUSP22 can inactivate T cells by two different mechanisms: indirectly through inducing UBR2 degradation (Brake I) and directly through dephosphorylating Lck (Brake II). In contrast, UBR2 protein accumulation and Lck ubiquitination/activation are induced in DUSP22-deficient T cells, leading to constitutive overactivation of the inflammatory T cells. The uncontrolled inflammation caused by DUSP22 deficiency is like a racing car losing its brakes. The researchers further validated that UBR2 overexpression, UBR2-Lck interaction, and Lck ubiquitination indeed occur in the peripheral blood T cells of SLE patients. Their findings indicate that DUSP22 deficiency and UBR2 overexpression play critical roles in the pathogenesis of autoimmune diseases.

The research team also characterized an autoimmune disease model using DUSP22/UBR2 double knockout mice. They found that the induction of proinflammatory cytokines and inflammatory responses in DUSP22 knockout mice was blocked by further knocking out UBR2. These results suggest that an inhibitor that suppresses UBR2 expression or activity in T cells may be a potential therapeutic drug for autoimmune diseases. This novel therapeutic approach could lead to precision medicine of autoimmune diseases.

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