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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 42; pp. E5706 - E5714
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.10.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Cells; Chronic Disease; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Female; Gene expression; Genetic Predisposition to Disease; Lymphocytes; Lymphopenia - genetics; Male; Mice; Mice, Mutant Strains; Mutation; PNAS Plus; Receptors, Peptide - genetics; Rodents; Viral infections; Virus Diseases - genetics; Virus Diseases - prevention & control; T-cell survival; positive selection; lymphocytes; N-ethyl-N-nitrosourea; T-cell development
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1515619112

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).Kdelr1homozygous 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, withKdelr1mutant mice unable to clear an otherwise self-limiting viral infection. These data reveal a nonredundant cellular function for KDELR1, upon which lymphocytes distinctly depend.