CD56 regulates human NK cell cytotoxicity through Pyk2

  1. Justin T Gunesch
  2. Amera L Dixon
  3. Tasneem AM Ebrahim
  4. Melissa Berrien-Elliott
  5. Swetha Tatineni
  6. Tejas Kumar
  7. Everardo Hegewisch-Solloa
  8. Todd A Fehniger
  9. Emily M Mace  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Columbia University, United States
  3. Barnard College, United States
  4. Washington University, United States
  5. Rice University, United States
  6. Washington University School of Medicine, United States

Abstract

Human natural killer (NK) cells are defined as CD56+CD3−. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Justin T Gunesch

    Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Amera L Dixon

    Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tasneem AM Ebrahim

    Biology, Barnard College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Melissa Berrien-Elliott

    Medicine, Washington University, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Swetha Tatineni

    Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tejas Kumar

    Pediatrics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Everardo Hegewisch-Solloa

    Pediatrics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Todd A Fehniger

    Dept of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8705-2887
  9. Emily M Mace

    Pediatrics, Columbia University, New York, United States
    For correspondence
    em3375@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0226-7393

Funding

National Institutes of Health (R01AI137073)

  • Emily M Mace

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Peripheral blood NK cells were obtained in accordance with the Declaration of Helsinki with the written and informed consent of all participants under the guidance of the Institutional Review Boards of Baylor College of Medicine (IRB H-30487) and Columbia University (IRB AAAR7377).

Copyright

© 2020, Gunesch et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 6,259
    views
  • 727
    downloads
  • 42
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Justin T Gunesch
  2. Amera L Dixon
  3. Tasneem AM Ebrahim
  4. Melissa Berrien-Elliott
  5. Swetha Tatineni
  6. Tejas Kumar
  7. Everardo Hegewisch-Solloa
  8. Todd A Fehniger
  9. Emily M Mace
(2020)
CD56 regulates human NK cell cytotoxicity through Pyk2
eLife 9:e57346.
https://doi.org/10.7554/eLife.57346

Share this article

https://doi.org/10.7554/eLife.57346

Further reading

    1. Cell Biology
    Inês Sequeira
    Insight

    A combination of intermittent fasting and administering Wnt3a proteins to a bone injury can rejuvenate bone repair in aged mice.

    1. Cell Biology
    Shixuan Liu, Ceryl Tan ... Ran Kafri
    Research Advance

    Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.