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NKD2 mediates stimulation-dependent ORAI1 trafficking to augment Ca2+ entry in T cells

Beibei Wu1, Jin Seok Woo1, Pamela Vila1

  • 1Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles CA 90095, USA.

Cell Reports
|August 25, 2021
PubMed

Insights

Naked cuticle homolog 2 (NKD2) enables sustained calcium (Ca2+) signaling in T cells by trafficking the ORAI1 channel to the plasma membrane, crucial for immune responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Sustained calcium (Ca2+) influx via CRAC channels is critical for effector T cell function.
  • The mechanisms controlling sustained CRAC channel activity, particularly ORAI1 localization, are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms regulating ORAI1 plasma membrane localization and sustained CRAC channel activity in effector T cells.
  • To identify novel proteins involved in ORAI1 trafficking and T cell activation.

Main Methods:

  • Targeted genetic screening to identify ORAI1-interacting proteins.
  • Confocal microscopy to visualize ORAI1 localization in T cells.
  • Biochemical assays to study protein interactions and trafficking pathways.

Main Results:

  • A significant portion of ORAI1 is retained in intracellular vesicles within effector T cells.
  • Naked cuticle homolog 2 (NKD2) was identified as a key component of ORAI1-containing vesicles.
  • NKD2 facilitates the trafficking and plasma membrane insertion of ORAI1 upon T cell receptor stimulation.

Conclusions:

  • NKD2 acts as an adaptor molecule, mediating TCR-dependent ORAI1 insertion into the plasma membrane.
  • This NKD2-driven ORAI1 trafficking is essential for sustained Ca2+ signaling and subsequent cytokine production in T cells.
Keywords:
ORAI1, STIM1, T cell receptor signaling, NKD2, CRAC channels, effector T cells, store-operated calcium entry, intracellular vesicles

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