Identification of a cytoplasmic Tyr-X-X-Leu motif essential for down regulation of the human cell receptor CD46 in persistent measles virus infection.

To investigate the sequence requirements for measles virus (MV)-induced receptor down regulation, we transfected the human CD46 gene into simian cells persistently infected by the Biken strain of MV. Surface expression of CD46 is drastically reduced in these cells. Deletion analysis has shown that the juxtamembrane region of the CD46 cytoplasmic domain is essential for down regulation. Deleting a Tyr-Arg-Tyr-Leu sequence in this region or changing these residues to Ala prevents CD46 down regulation from the infected cell surface. Alanine-scanning mutagenesis has identified two amino acid residues, Tyr and Leu, forming a Tyr-X-X-Leu motif critical for CD46 down regulation. Mutations that prevent CD46 down regulation enhance syncytium formation. These results indicate that CD46 down regulation limits the cytopathic effects in a persistent MV infection and that CD46 down regulation requires a cytoplasmic Tyr-X-X-Leu sequence which resembles known motifs for membrane protein trafficking and receptor signalling.