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The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse

  1. Marcus Lettau *,
  2. Jing Qian *,
  3. Andreas Linkermann *,
  4. Mathieu Latreille † ,
  5. Louise Larose † ,
  6. Dieter Kabelitz *, and
  7. Ottmar Janssen * , ‡
  1. *Institute for Immunology, University Hospital Schleswig–Holstein Campus Kiel, 24105 Kiel, Germany; and
  2. †Polypeptide Laboratory, McGill University, Montreal, QC, Canada H3A 2B2

  1. Edited by Stuart F. Schlossman, Dana–Farber Cancer Institute, Boston, MA, and approved February 21, 2006 (received for review October 3, 2005)

Abstract

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell–cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase- and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.

Footnotes

  • ‡To whom correspondence should be addressed at: Institute for Immunology, University Hospital Schleswig–Holstein Campus Kiel, Michaelisstrasse 5, 24105 Kiel, Germany. E-mail: ojanssen{at}email.uni-kiel.de

  • Author contributions: M. Lettau, D.K., and O.J. designed research; M. Lettau, J.Q., A.L., and O.J. performed research; M. Latreille and L.L. contributed new reagents/analytic tools; M. Lettau, J.Q., D.K., and O.J. analyzed data; and O.J. wrote the paper.

  • Conflict of interest statement: No conflicts declared.

  • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations:

    Abbreviations:

    FasL,
    Fas ligand;
    IS,
    immunological synapse;
    TCR,
    T cell receptor;
    WASp,
    Wiskott–Aldrich syndrome protein;
    SH,
    Src homology;
    siRNA,
    short interfering RNA;
    PHA,
    phytohemagglutinin;
    lamp-1,
    lysosome-associated membrane protein 1;
    EBV,
    Epstein–Barr virus;
    B-LCL,
    lymphoblastoid B cell line.

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