Cbl ubiquitin ligases mediate the inhibition of natural killer cell activity

Omri Matalon, Mira Barda-Saad

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Natural killer (NK) cells are essential for killing transformed and virally infected cells. To prevent autoreactivity, NK cell activation is inhibited by inhibitory receptors that activate the tyrosine phosphatase SHP-1, which dephosphorylates signaling molecules crucial for NK cell activation. Initially, only a single SHP-1 substrate was identified in NK cells, the GEF VAV1. We recently demonstrated that under inhibitory conditions, LAT, PLCγ1 and PLCγ2 serve as novel SHP-1 substrates in NK cells. Furthermore, we showed that during NK cell inhibition, LAT is ubiquitylated by c-Cbl and Cbl-b, leading to its proteasomal degradation, abolishing NK cell cytotoxicity. Here, we address the mechanism through which the Cbl proteins are activated following inhibitory receptor engagement. We demonstrate that during NK cell inhibition, the expression level of the Cbl proteins significantly increases. These data suggest that inhibitory KIR receptors regulate the stability of the Cbl proteins, thereby enabling Cbl-mediated inhibition of NK cell cytotoxicity.

Original languageEnglish
JournalCommunicative and Integrative Biology
Volume9
Issue number6
DOIs
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© 2016 Omri Matalon and Mira Barda-Saad.

Keywords

  • Cbl-b
  • Cytotoxicity
  • E3 ubiquitin ligase
  • NK cell inhibition
  • NK cell signaling
  • Natural killer cells
  • Ubiquitylation
  • c-Cbl

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