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Characterization of a Dipeptide Motif Regulating IFN- Receptor 2 Plasma Membrane Accumulation and IFN- Responsiveness¹

Sergio D. Rosenzweig^2,*, Owen M. Schwartz, Margaret R. Brown, Thomas L. Leto^* and Steven M. Holland^3,*,

^* Laboratory of Host Defenses, Laboratory of Clinical Infectious Diseases, and Biological Imaging Facility, National Institutes of Allergy and Infectious Diseases; and Clinical Immunology Laboratory, Warren Grant Magnuson Clinical Center, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892

The IFN-R complex is composed of two IFN-R1 and two IFN-R2 polypeptide chains. Although IFN-R1 is constitutively expressed on all nucleated cells, IFN-R2 membrane display is selective and tightly regulated. We created a series of fluorescent-tagged IFN-R2 expression constructs to follow the molecule’s cell surface expression and intracellular distribution. Truncation of the receptor immediately upstream of Leu-Ile 255–256 (254X) created a receptor devoid of signaling that overaccumulated on the cell surface. In addition, this truncated receptor inhibited wild-type IFN-R2 activity and therefore exerted a dominant negative effect. In-frame deletion (2552) or alanine substitution (LI255–256AA) of these amino acids created mutants that overaccumulated on the plasma membrane, but had enhanced function. Single amino acid substitutions (L255A or I256A) had a more modest effect. In-frame deletions upstream (2532), but not downstream (2572), of Leu-Ile 255–256 also led to overaccumulation. A truncation within the IFN-R2 Jak2 binding site (270X) led to a mutant devoid of function that did not overaccumulate and did not affect wild-type IFN-R2 signaling. We have created a series of novel mutants of IFN-R2 that have facilitated the identification of intracellular domains that control IFN-R2 accumulation and IFN- responsiveness. In contrast to IFN-R1, not only dominant negative, but also dominant gain-of-function, mutations were created through manipulation of IFN-R2 Leu-Ile 255–256. These IFN-R2 mutants will allow fine dissection of the role of IFN- signaling in immunity.

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