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

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

Author information

1
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom; Bruce.Beutler@UTSouthwestern.edu owen.siggs@gmail.com.
2
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
3
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;
4
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
7
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390 Bruce.Beutler@UTSouthwestern.edu owen.siggs@gmail.com.

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

PMID:
26438836
PMCID:
PMC4620900
DOI:
10.1073/pnas.1515619112
[Indexed for MEDLINE]
Free PMC Article

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