Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection

Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5706-14. doi: 10.1073/pnas.1515619112. Epub 2015 Oct 5.

Abstract

Endoplasmic reticulum (ER)-resident proteins are continually retrieved from the Golgi and returned to the ER by Lys-Asp-Glu-Leu (KDEL) receptors, which bind to an eponymous tetrapeptide motif at their substrate's C terminus. Mice and humans possess three paralogous KDEL receptors, but little is known about their functional redundancy, or if their mutation can be physiologically tolerated. Here, we present a recessive mouse missense allele of the prototypical mammalian KDEL receptor, KDEL ER protein retention receptor 1 (KDELR1). Kdelr1 homozygous mutants were mildly lymphopenic, as were mice with a CRISPR/Cas9-engineered frameshift allele. Lymphopenia was cell intrinsic and, in the case of T cells, was associated with reduced expression of the T-cell receptor (TCR) and increased expression of CD44, and could be partially corrected by an MHC class I-restricted TCR transgene. Antiviral immunity was also compromised, with Kdelr1 mutant mice unable to clear an otherwise self-limiting viral infection. These data reveal a nonredundant cellular function for KDELR1, upon which lymphocytes distinctly depend.

Keywords: N-ethyl-N-nitrosourea; T-cell development; T-cell survival; lymphocytes; positive selection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Endoplasmic Reticulum / metabolism*
  • Female
  • Genetic Predisposition to Disease*
  • Lymphopenia / genetics*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Receptors, Peptide / genetics*
  • Virus Diseases / genetics
  • Virus Diseases / prevention & control*

Substances

  • KDELR1 protein, human
  • Receptors, Peptide