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Stressed out: NKp46 binds ecto-calreticulin.

Dillon Corvino1, Denise Rommel1, Franziska Schneppenheim1

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Immunology and Cell Biology
|May 25, 2023
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Summary

Natural killer (NK) cell receptor NKp46 binds externalized calreticulin (ecto-CRT) on stressed cells. This interaction triggers NK cell degranulation, promoting the elimination of damaged or infected cells.

Keywords:
Ecto-calreticulinNK cell activating receptorsNKP46

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Natural killer (NK) cells are crucial for innate immunity, identifying and eliminating stressed, infected, or malignant cells.
  • Calreticulin (CRT) is a protein typically found within the endoplasmic reticulum.
  • Externalized calreticulin (ecto-CRT) has been observed on stressed cells, but its specific role in NK cell recognition was unclear.

Purpose of the Study:

  • To investigate the interaction between the NK cell receptor NKp46 and externalized calreticulin (ecto-CRT).
  • To elucidate the mechanism by which ecto-CRT signals NK cells to eliminate target cells.

Main Methods:

  • Utilized co-immunoprecipitation and flow cytometry to assess NKp46-ecto-CRT binding.
  • Employing cellular assays to measure NK cell degranulation and target cell lysis upon NKp46 engagement.
  • Inducing endoplasmic reticulum stress in target cells to promote ecto-CRT exposure.

Main Results:

  • Demonstrated direct binding of the activating NK cell receptor NKp46 to ecto-CRT.
  • Showed that NKp46-ecto-CRT interaction leads to NK cell degranulation and subsequent target cell killing.
  • Confirmed that endoplasmic reticulum stress-induced ecto-CRT functions as a danger-associated molecular pattern.

Conclusions:

  • The NKp46 receptor recognizes ecto-CRT as a signal of cellular distress.
  • This recognition pathway facilitates NK cell-mediated elimination of compromised cells, including those that are infected, malignant, stressed, or senescent.
  • Highlights a novel mechanism for NK cell-mediated immunity involving ecto-CRT as a key molecular target.