The endoplasmic reticulum adaptor protein ERAdP initiates NK cell activation via the Ubc13-mediated NF-κB pathway

J Immunol. 2015 Feb 1;194(3):1292-303. doi: 10.4049/jimmunol.1402593. Epub 2014 Dec 29.

Abstract

NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-κB pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-κB essential modulator ubiquitination to trigger the Ubc13-mediated NF-κB pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cytotoxicity, Immunologic / genetics
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation
  • Gene Expression
  • Humans
  • I-kappa B Kinase / metabolism
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Activation / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • Protein Binding
  • Signal Transduction*
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • ERAdP protein, human
  • Membrane Proteins
  • NF-kappa B
  • Interferon-gamma
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • I-kappa B Kinase