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. 2008 Jul;82(14):6862-8.
doi: 10.1128/JVI.00397-08. Epub 2008 May 7.

Identification of the myelin protein plasmolipin as the cell entry receptor for Mus caroli endogenous retrovirus

A Dusty Miller  1 , Ulla Bergholz, Marion Ziegler, Carol Stocking
Affiliations

Identification of the myelin protein plasmolipin as the cell entry receptor for Mus caroli endogenous retrovirus

A Dusty Miller et al. J Virol. 2008 Jul.

Abstract

The Asian wild mouse species Mus caroli harbors an endogenous retrovirus (McERV) that is closely related to but distinct from the endogenous retrovirus family defined by the Mus dunni endogenous virus and the Mus musculus endogenous retrovirus. McERV could infect some cell types from humans, dogs, and rats, but not all, and did not infect any mouse cell line tested. Because of its interesting host range and proposed ancestral relationship to primate retroviruses and because none of the entry receptors for this family of retroviruses had been identified, we began a search for the McERV receptor. We determined the chromosomal location of the receptor gene in the human genome by phenotypic screening of the G3 human-hamster radiation hybrid cell line panel and confirmed the localization by assaying for receptor activity conferred by bacterial artificial chromosome (BAC) clones spanning the region. We next localized the gene more precisely in one positive BAC by assaying for receptor activity following BAC digestion with several restriction enzymes that cleaved different sets of genes, and we confirmed that the final candidate gene, plasmolipin (PLLP; TM4SF11), is the novel receptor by showing that the expression of the human PLLP cDNA renders hamster and mouse cells susceptible to McERV infection. PLLP functions as a voltage-dependent potassium ion channel and is expressed primarily in kidney and brain, helping to explain the limited range of cell types that McERV can infect. Interestingly, mouse PLLP also functioned well as a receptor for McERV but was simply not expressed in the mouse cell types that we originally tested.

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Figures

FIG. 1.
FIG. 1.
McERV receptor localization to human chromosome 16q13. Analysis of 40 of the G3 RH cell lines linked the McERV receptor to the following unique SHGC markers, with the indicated LOD scores, ranked from highest to lowest: SHGC-34581, 8.03 (1); SHGC-14687, 7.46 (2); SHGC-15371, 6.35 (3); SHGC-20957 and SHGC-37413, 5.56 (4); SHGC-58086, 4.80 (5); SHGC-14315, 4.31 (6); SHGC-14216 and SHGC-247, 3.78 (7); and SHGC-20956, 3.69 (8). The positions of markers ranked 1 to 5 are shown on human chromosome 16. DNA sequence numbers are indicated in megabases starting from the tip of the p arm of chromosome 16 (human genome build 36.2). Known genes in this region are depicted with filled boxes indicating exons, open boxes indicating nontranslated regions in exons, lines indicating introns, and arrows indicating the direction of gene transcription. BAC clones spanning this region are indicated to the right. The original names of the clones begin with “RP11-,” which has been deleted for simplicity. Data used to generate this figure are from the NCBI map viewer and the UCSC genome browser.
FIG. 2.
FIG. 2.
Susceptibility of cells to McERV infection correlates with PLLP RNA expression. Reverse transcription-PCR detection of PLLP and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) (positive control) in mRNA from cell lines or from mouse kidney was performed with primers designed for hPLLP, mPLLP, and GAPDH cDNAs. No PLLP-specific signal was detected for A23 cells using human (shown) or mouse (not shown) primers.
FIG. 3.
FIG. 3.
Phylogeny of mammalian PLLPs and related proteins. Amino acid sequences of proteins closely related to mPLLP and hPLLP were obtained from the GenBank database using BLAST searches and were compared using ClustalW. Also shown is CKLFSF8, the most closely related non-PLLP protein. Species for which derived cell lines are susceptible to McERV infection are underlined. The rest of the species shown have not been tested for McERV susceptibility. The scale bar at the lower left indicates 10% amino acid divergence.
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