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

Owen M. Siggs, Daniel L. Popkin, Philippe Krebs, Xiaohong Li, Miao Tang, Xiaoming Zhan, Ming Zeng, Pei Lin, Yu Xia, Michael B A Oldstone, Richard J. Cornall, Bruce Beutler

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E5706-E5714
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number42
DOIs
StatePublished - Oct 20 2015

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Lymphopenia
Virus Diseases
Endoplasmic Reticulum
Mutation
T-Cell Antigen Receptor
lysyl-aspartyl-glutamyl-leucine
Clustered Regularly Interspaced Short Palindromic Repeats
Alleles
Transgenes
Antiviral Agents
Immunity
Proteins
Lymphocytes
T-Lymphocytes
KDEL receptor

Keywords

  • Lymphocytes
  • N-ethyl-N-nitrosourea
  • Positive selection
  • T-cell development
  • T-cell survival

ASJC Scopus subject areas

  • General

Cite this

Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection. / Siggs, Owen M.; Popkin, Daniel L.; Krebs, Philippe; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Zeng, Ming; Lin, Pei; Xia, Yu; Oldstone, Michael B A; Cornall, Richard J.; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 42, 20.10.2015, p. E5706-E5714.

Research output: Contribution to journalArticle

Siggs, Owen M. ; Popkin, Daniel L. ; Krebs, Philippe ; Li, Xiaohong ; Tang, Miao ; Zhan, Xiaoming ; Zeng, Ming ; Lin, Pei ; Xia, Yu ; Oldstone, Michael B A ; Cornall, Richard J. ; Beutler, Bruce. / Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 42. pp. E5706-E5714.
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