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 (2015). Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 112(42), E5706-E5714. National Academy of Sciences NAS 10.1073/pnas.1515619112

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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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Krebs, Philippe




National Academy of Sciences NAS




Doris Haefelin

Date Deposited:

07 Dec 2015 12:26

Last Modified:

05 Dec 2022 14:50

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

N-ethyl-N-nitrosourea T-cell development T-cell survival lymphocytes positive selection




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