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MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway

Yanru Guo1,2, Laia Ollé1,2, Elizabeth Proaño-Pérez1,2,3

  • 1Biochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.

Frontiers in Immunology
|May 26, 2023
PubMed

Insights

The study reveals that activating MRGPRX2 receptor leads to increased microphthalmia-associated transcription factor (MITF) activity, crucial for mast cell degranulation. Inhibiting this pathway could treat MRGPRX2-related diseases.

Area of Science:

  • Immunology
  • Cell Biology
  • Pharmacology

Background:

  • The Mas-related G protein-coupled receptor X2 (MRGPRX2) is involved in skin immunity, pain, and non-IgE-mediated hypersensitivity reactions.
  • MRGPRX2 plays a role in adverse drug reactions and inflammatory skin conditions like chronic spontaneous urticaria and atopic dermatitis.
  • The precise signaling pathways downstream of MRGPRX2 activation remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the signaling transduction pathway of MRGPRX2 activation in mast cells.
  • To investigate the role of Lysyl t-RNA synthetase (LysRS) and microphthalmia-associated transcription factor (MITF) in MRGPRX2-mediated mast cell responses.
  • To explore potential therapeutic targets for MRGPRX2-associated pathologies.

Main Methods:

  • Investigated MRGPRX2 activation using substance P and identified downstream signaling events in mast cells.
  • Utilized techniques such as Western blotting, calcium influx assays, and mast cell degranulation assays.
  • Employed gene silencing (siRNA) and pharmacological inhibition (ML329) to assess the role of MITF.

Main Results:

  • MRGPRX2 activation by substance P promoted the nuclear translocation and activation of Lysyl t-RNA synthetase (LysRS).
  • MRGPRX2 signaling led to MITF phosphorylation and increased MITF activity, which was dependent on LysRS.
  • Silencing MITF or inhibiting its pathway with ML329 significantly reduced MRGPRX2-induced calcium influx and mast cell degranulation.
  • Known MRGPRX2-activating drugs (e.g., atracurium, vancomycin, morphine) also increased MITF activity.

Conclusions:

  • MRGPRX2 signaling activates the LysRS-MITF pathway, leading to mast cell degranulation.
  • MITF acts as a key mediator in MRGPRX2-dependent mast cell responses.
  • Targeting the MITF pathway presents a potential therapeutic strategy for diseases involving MRGPRX2 activation.
Keywords:
LysRSMITFMRGPRX2adverse drug reactionsmast cell degranulation

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