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 language | English (US) |
|---|---|
| Pages (from-to) | E5706-E5714 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 112 |
| Issue number | 42 |
| DOIs | |
| State | Published - Oct 20 2015 |
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Keywords
- Lymphocytes
- N-ethyl-N-nitrosourea
- Positive selection
- T-cell development
- T-cell survival
ASJC Scopus subject areas
- General
Cite this
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.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 42, 20.10.2015, p. E5706-E5714.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection
AU - Siggs, Owen M.
AU - Popkin, Daniel L.
AU - Krebs, Philippe
AU - Li, Xiaohong
AU - Tang, Miao
AU - Zhan, Xiaoming
AU - Zeng, Ming
AU - Lin, Pei
AU - Xia, Yu
AU - Oldstone, Michael B A
AU - Cornall, Richard J.
AU - Beutler, Bruce
PY - 2015/10/20
Y1 - 2015/10/20
N2 - 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.
AB - 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.
KW - Lymphocytes
KW - N-ethyl-N-nitrosourea
KW - Positive selection
KW - T-cell development
KW - T-cell survival
UR - http://www.scopus.com/inward/record.url?scp=84947246337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947246337&partnerID=8YFLogxK
U2 - 10.1073/pnas.1515619112
DO - 10.1073/pnas.1515619112
M3 - Article
C2 - 26438836
AN - SCOPUS:84947246337
VL - 112
SP - E5706-E5714
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 42
ER -