Autoimmunity: Redoxing PTPN22 activity

The oxidative state of a critical cysteine residue determines the enzymatic activity of a phosphatase involved in T-cell immune responses.
  1. Magdalena Shumanska
  2. Ivan Bogeski  Is a corresponding author
  1. Molecular Physiology Division, Institute of Cardiovascular Physiology, University Medical Center, Georg-August University, Germany

A precisely tuned immune system is tremendously important for rapidly sensing and eliminating disease-causing pathogens and generating immunological memory. At the same time, immune cells need to be able to recognize the body’s own cells and distinguish them from foreign invaders. Even small dysregulations can result in the immune system attacking organs and tissues in the body by mistake, leading to conditions known as autoimmune diseases.

The incidence of autoimmune diseases worldwide has increased in recent years, leading scientists to investigate how genetic and environmental factors contribute to these pathologies (Ye et al., 2018). Amongst other findings, research has shown that an enzyme called PTPN22 (short for protein tyrosine phosphatase non-receptor type 22) is a risk factor in multiple autoimmune disorders, including rheumatoid arthritis, diabetes and systemic lupus erythematosus. PTPN22 prevents the overactivation of T-cells (cells of the adaptive immune system) by removing phosphate groups from phosphorylated proteins that are part of the T-cell receptor (TCR) signaling pathway (Figure 1; Bottini et al., 2006; Fousteri et al., 2013; Tizaoui et al., 2021).

A model of PTPN22 redox regulation and its effect on T-cell activity.

In normal immunity, wildtype PTPN22 (left, blue protein with green lettering) is able to efficiently remove phosphate groups (yellow circles) from proteins downstream of the T-cell receptor (TCR), including LCK, Fyn and Zap70. Dephosphorylation inactivates these proteins, reducing T-cell activity. In this state, two PTPN22 cysteine residues (at positions 129 and 227) form a disulfide bond, which influences the redox state and the activity of the enzyme. If PTPN22 is mutated so that cysteine 129 becomes a serine (right, blue protein with red lettering, with the mutant serine residue shown in red), the disulfide bond cannot form, and the phosphatase becomes more sensitive to deactivation by oxidation. The mutant version of the phosphatase is also less efficient at dephosphorylating proteins, which increases TCR signaling and inflammation, leading to autoimmunity.

Figure created using BioRender

Activation of the T-cell receptor is followed by the production of reactive oxygen species (ROS), highly reactive by-products of molecular oxygen, which can oxidize other molecules, including proteins. It is now clear that ROS have important roles in T-cell activation and that defects in ROS production may alter the immune system's responses (Simeoni and Bogeski, 2015; Kong and Chandel, 2018). However, high levels of ROS can also cause oxidative stress, leading to impaired cell activity and even death. Therefore, T-cells must optimally balance ROS production through antioxidative mechanisms and enzymes such as thioredoxin (Patwardhan et al., 2020).

Redox reactions (oxidation and its reverse reaction known as reduction) regulate many proteins, including phosphatases (Tonks, 2005), although how oxidation and reduction modulate PTPN22 activity remained unclear. Now, in eLife, Rikard Holmdahl and colleagues based in Sweden, China, Australia, Austria, France, Russia, Hungary and the United States – including Jaime James (Karolinska Institute) as first author – report that a non-catalytic cysteine may play an important role in the redox regulation of PTPN22 (James et al., 2022). Notably, this regulation was found to modulate inflammation in mouse models with severe autoimmunity.

The team genetically engineered mice that carried a mutated version of PTPN22, in which a non-catalytic cysteine at position 129 was replaced with a serine, preventing that residue from forming a disulfide bond with the catalytic cysteine at position 227 responsible for the enzymatic activity of PTPN22. Notably, this approach was based on a study in which the crystal structure of PTPN22 was examined and an atypical bond was observed between the non-catalytic cysteine at position 129 and the catalytic cysteine residue (C227; Orrú et al., 2009). In vitro experiments performed by James et al. revealed that the mutant enzyme was more sensitive to inhibition by oxidation than its wildtype counterpart. Interestingly, the results also showed that the mutant PTPN22 was less efficient at performing its catalytic role, and that it was less responsive to re-activation by antioxidant enzymes, such as thioredoxin.

To further test the role of cysteine 129 in PTPN22 redox regulation, James et al. used a mouse model that expressed the mutant protein and was susceptible to rheumatoid arthritis. These mice exhibited higher levels of inflammation in response to T-cell activation, which would be expected in animals that cannot downregulate TCR signaling. The mice also displayed more severe symptoms of arthritis, consistent with high immune activity. These effects were not observed when the experiment was repeated in mice that fail to produce high levels of ROS in response to TCR activation, confirming that the initial observations depend on the redox state of PTPN22.

Finally, James et al. performed in vitro experiments on T-cells isolated from mice carrying the mutant PTPN22. They found that when these cells became activated, the downstream targets of PTPN22 showed an increased phosphorylation status, consistent with lower PTPN22 activity.

Taken together, the elegant study of James et al. shows that cysteine 129 is critical for the redox regulation of PTPN22, and that its mutation impacts T-cell activity and exacerbates autoimmunity in mice (Figure 1). What still remains to be determined is why the mutant enzyme has lower catalytic activity, which may be due to the mutation affecting the structural conformation of PTPN22. Additionally, it will be important to assess other cysteines in PTPN22 to determine whether they are also partly involved in its redox regulation.

Understanding how the redox state of PTPN22 regulates the activity of T-cells may help researchers to develop new therapies for treating autoimmune diseases.

References

Article and author information

Author details

  1. Magdalena Shumanska

    Magdalena Shumanska is in Molecular Physiology Division, Institute of Cardiovascular Physiology, University Medical Center, Georg-August University, Göttingen, Germany

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7999-6781
  2. Ivan Bogeski

    Ivan Bogeski is in Molecular Physiology Division, Institute of Cardiovascular Physiology, University Medical Center, Georg-August University, Göttingen, Germany

    For correspondence
    ivan.bogeski@med.uni-goettingen.de
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9879-7174

Publication history

  1. Version of Record published: May 19, 2022 (version 1)

Copyright

© 2022, Shumanska and Bogeski

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 577
    views
  • 99
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Magdalena Shumanska
  2. Ivan Bogeski
(2022)
Autoimmunity: Redoxing PTPN22 activity
eLife 11:e79125.
https://doi.org/10.7554/eLife.79125

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Tobias Weinberger, Messerer Denise ... Christian Schulz
    Research Article

    Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

    1. Immunology and Inflammation
    Tong Feng, Qi Zhang ... Qiao-Feng Wu
    Research Article

    Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p. Thus, these results indicated that MiR-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.