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A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.

ABSTRACT: The cytoplasmic kinase ZAP70 is critical for T cell antigen receptor (TCR) signaling. The R360P mutation in ZAP70 is responsible for an early-onset familial autoimmune syndrome. The structural location and biochemical signaling effects of the R360P mutation are consistent with weakening of the autoinhibitory conformation of ZAP70. Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling. In addition, the R360P mutation resulted in enhanced follicular helper T cell expansion after LCMV infection. To eliminate the possibility of a TCR repertoire shift, the OTI transgenic TCR was introduced into R360P mice, which resulted in enhanced T cell responses to weaker stimuli, including weak agonists and a self-peptide. These observations suggest that disruption of ZAP70 autoinhibition by the R360P mutation enables increased mature T cell sensitivity to self-antigens that would normally be ignored by wild-type T cells, a mechanism that may contribute to the break of tolerance in human patients with R360P mutation.

SUBMITTER: Shen L

PROVIDER: S-EPMC8009134 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.

Shen Lin L Matloubian Mehrdad M Kadlecek Theresa A TA Weiss Arthur A

Science signaling 20210202 668

The cytoplasmic kinase ZAP70 is critical for T cell antigen receptor (TCR) signaling. The R360P mutation in ZAP70 is responsible for an early-onset familial autoimmune syndrome. The structural location and biochemical signaling effects of the R360P mutation are consistent with weakening of the autoinhibitory conformation of ZAP70. Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling. In addition, ...[more]

PMID: 33531381

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Project description:Pharmacological suppression of γ-aminobutyric acid (GABA) transaminase (GABA-T), the sole GABA-degrading enzyme and a potential therapeutic target for treating brain disorders such as epilepsy, increases not only phasic inhibition but also tonic inhibition. However, the specific cellular source, neuromodulatory effects and potential therapeutic benefits of this enhanced tonic inhibition remain unexplored due to the lack of cell-type-specific gene manipulation studies. Here we report that the increase in tonic GABA currents observed after GABA-T suppression is predominantly due to increased tonic GABA release from astrocytes rather than action-potential-dependent synaptic GABA spillover. General GABA-T knockdown (KD) by a short hairpin RNA considerably increased tonic GABA currents in dentate granule cells, thereby enhancing tonic inhibition. An astrocyte-specific rescue of GABA-T following general GABA-T KD normalized the elevated tonic GABA currents to near control levels. Tetrodotoxin-insensitive tonic GABA currents were significantly increased after general GABA-T KD, whereas tetrodotoxin-sensitive tonic GABA currents showed no significant increase, suggesting that this enhanced tonic inhibition is primarily action-potential independent. General GABA-T KD reduced the spike probability of granule cells and impaired dorsal hippocampus-dependent spatial memory, which were fully reversed by astrocyte-specific GABA-T rescue. These findings suggest that suppressing astrocytic GABA-T may be sufficient to influence the excitatory/inhibitory balance in the brain and associated behaviors. Our study implies that the therapeutic benefits of pharmacological GABA-T suppression may be largely attributed to the modulation of astrocytic GABA-T and its impact on tonic GABA release from astrocytes. Here, we report distinct effects of GABA-T suppression depending on cell type; suppressing GABA-T in astrocytes enhances tonic inhibition, while its suppression in GABAergic neurons augments phasic inhibition. Our findings demonstrate that targeted suppression of astrocytic GABA-T not only enhances tonic GABA release from astrocytes but also significantly influences the excitation/inhibition balance in the brain, with consequential effects on behavior. This suggests that astrocytic GABA-T modulation holds promising potential for developing novel therapeutic strategies aimed at treating cognitive and neurological disorders through the regulation of astrocytic GABA metabolism. GAD glutamate decarboxylase, MAO-B monoamine oxidase B, BEST1 bestrophin 1, GABA-T GABA transaminase, GAT GABA transporter, DG dentate gyrus, SSA succinic semialdehyde.

Dataset Information

A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.

Publications

A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.

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