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.
- 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).
Figure 1
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
-
Role of PTPN22 in type 1 diabetes and other autoimmune diseasesSeminars in Immunology 18:207–213.https://doi.org/10.1016/j.smim.2006.03.008
-
Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunityClinical Immunology 149:556–565.https://doi.org/10.1016/j.clim.2013.10.006
-
Regulation of redox balance in cancer and T cellsThe Journal of Biological Chemistry 293:7499–7507.https://doi.org/10.1074/jbc.TM117.000257
-
A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosusHuman Molecular Genetics 18:569–579.https://doi.org/10.1093/hmg/ddn363
-
Redox regulation of regulatory T-cell differentiation and functionsFree Radical Research 54:947–960.https://doi.org/10.1080/10715762.2020.1745202
-
Redox regulation of T-cell receptor signalingBiological Chemistry 396:555–568.https://doi.org/10.1515/hsz-2014-0312
-
The role of PTPN22 in the pathogenesis of autoimmune diseases: a comprehensive reviewSeminars in Arthritis and Rheumatism 51:513–522.https://doi.org/10.1016/j.semarthrit.2021.03.004
Article and author information
Author details
Magdalena Shumanska
Publication history
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
-
- 646
- views
-
- 111
- downloads
-
- 1
- 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)
Autoimmunity: Redoxing PTPN22 activity
eLife 11:e79125.
https://doi.org/10.7554/eLife.79125
Further reading
-
- Immunology and Inflammation
The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
-
- Immunology and Inflammation
- Medicine
Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.
