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

Owen Siggs, Daniel Popkin, Philippe Krebs, Xiaohong Li, Miao Tang, Xiaoming Zhan, Ming Zeng, Pei Lin, Yu Xia, Michael Oldstone, Richard 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
    Pages (from-to)E5706-E5714
    Number of pages9
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume112
    Issue number42
    DOIs
    Publication statusPublished - 2015

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