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Published on: December 20, 2017
QRICH1 mediates an intracellular checkpoint for CD8+ T cell activation via the CARD11 signalosome
Nicole M Carter1, Wihib D Hankore1, Yong-Kang Yang1
1Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract:
Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain-containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8+ T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8+ T cells by regulating numerous genes critical for CD8+ T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.
Insights
Glutamine-rich protein 1 (QRICH1) acts as a checkpoint for CD8+ T cell activation by regulating Caspase recruitment domain-containing protein 11 (CARD11) signaling. This discovery refines understanding of immune response fine-tuning.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Lymphocyte activation relies on intricate signaling pathways involving scaffolds and negative regulators.
- Caspase recruitment domain-containing protein 11 (CARD11) is a key scaffold protein mediating T cell receptor (TCR) signaling to downstream pathways like NF-κB, JNK, mTOR, and Akt.
Purpose of the Study:
- To identify novel regulators of CARD11 signaling in T cell activation.
- To elucidate the role of glutamine-rich protein 1 (QRICH1) as an intracellular checkpoint for CD8+ T cell activation.
Main Methods:
- Investigated QRICH1's interaction with CARD11 following TCR engagement.
- Analyzed QRICH1's impact on NF-κB signaling and CD8+ T cell functions (activation, proliferation, effector status).
- Characterized the intramolecular interactions within QRICH1 that regulate its function.
Main Results:
- QRICH1 was identified as a negative regulator of CARD11 signaling, specifically inhibiting NF-κB activation.
- QRICH1 associates with CARD11 upon TCR stimulation, with its binding regulated by intramolecular domain interactions.
- QRICH1 critically controls antigen-induced CD8+ T cell activation, proliferation, and effector differentiation by modulating gene expression.
Conclusions:
- QRICH1 functions as an intracellular checkpoint in antigen receptor signaling, fine-tuning CD8+ T cell responses.
- This study reveals QRICH1 as a novel component of the signaling circuitry that governs T cell effector output.
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