A recently published paper concluded that Lgr4 is essential for vesicular stomatitis virus (VSV) entry to cells (1), in contrast with independently confirmed studies, showing that VSV infects cells through the LDL receptor (LDLR) and/or its family members (2–4). This report raises many concerns, suggesting that Lgr4 is not involved in VSV entry. I will address three key issues.1. VSV-G and Lgr4 ectodomains (ECD) have been expressed without the signal peptide. Hence, they did not translocate into the ER and, therefore, did not form correct disulfide bridges, nor acquire the oligosaccharide side chains, which are important for correct folding of the VSV-G ectodomain. Therefore, the described co-immunoprecipitations (Fig. 5B of Ref. 1) could stem from aggregation of the misfolded VSV-G–ECD and LGR4-ECD.2. The interpretation of the Biacore experiments (Fig. 5D of Ref. 1) is very difficult, as most of the binding shown is irreversible. The graph shows only association curves, whereas the dissociation curves are missing for all but the highest concentration. A quick look suggests a half-effect at 500–700 nm, and, therefore, the claimed Kd of ∼70 nm cannot be correct.3. Furthermore, the claimed 70 nm value is not consistent with the concentration required for VSV neutralization (200 μg/ml, ≅4 μm, Fig. 6A of Ref. 1). By comparison, the IC50 of LDLR-ECD is 55 ng/ml (2). Thus, on weight basis, LGR4-ECD is ∼3600 times less potent than LDLR-ECD. Therefore, the author's statement that “soluble LGR4-ECD … could inhibit VSV infection… showing great potential for treating vesicular stomatitis” is unfounded.
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