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) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology |
UniBE Contributor: |
Krebs, Philippe |
ISSN: |
0027-8424 |
Publisher: |
National Academy of Sciences NAS |
Language: |
English |
Submitter: |
Doris Haefelin |
Date Deposited: |
07 Dec 2015 12:26 |
Last Modified: |
05 Dec 2022 14:50 |
Publisher DOI: |
10.1073/pnas.1515619112 |
PubMed ID: |
26438836 |
Uncontrolled Keywords: |
N-ethyl-N-nitrosourea T-cell development T-cell survival lymphocytes positive selection |
BORIS DOI: |
10.7892/boris.73739 |
URI: |
https://boris.unibe.ch/id/eprint/73739 |