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Redox regulation of PTPN22 affects the severity of T cell dependent autoimmune inflammation

ABSTRACT: PTPN22, a modifier of T cell receptor signaling, and reactive oxygen species are major players in the regulation of chronic autoimmune diseases. As with all protein tyrosine phosphatases the activity of PTPN22 is redox regulated, but if or how such regulation can modulate inflammatory pathways in vivo is not known. To determine this, we created a mouse with a cysteine-to-serine mutation at position 129 in PTPN22 (C129S), a residue proposed to alter the redox regulatory properties of PTPN22 by forming a disulfide with the catalytic C227 residue. The C129S mutant mouse showed a stronger T cell-dependent inflammatory response due to enhanced TCR signaling and activation of T cells. Activity assays with purified proteins suggest that the functional results can be explained by an increased sensitivity to oxidation of the C129S mutated PTPN22 protein. We also observed that the disulfide of native PTPN22 can be directly reduced by the thioredoxin system, while the C129S mutant lacking this disulfide was less amenable to reductive reactivation. In conclusion, we show in the mouse that the non-catalytic C129 residue of PTPN22 modulates its redox regulatory properties, and that oxidation-prone PTPN22 leads to increased severity in the development of T cell-dependent autoimmunity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Blood Cell

SUBMITTER: Amir Ata Saei

LAB HEAD: Prof. Roman. A. Zubarev

PROVIDER: PXD025319 | Pride | 2022-03-23

REPOSITORIES: Pride

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