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Annexin V Associates with the IFN- Receptor and Regulates IFN- Signaling¹

Carlos Leon^2,*,, Devki Nandan^2,*, Martin Lopez^*, Alireza Moeenrezakhanlou^* and Neil E. Reiner^3,*,

^* Department of Medicine, Division of Infectious Diseases, and Department of Microbiology and Immunology, University of British Columbia Faculties of Medicine and Science, and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada

Many of the biological activities of IFN- are mediated through the IFN-R3-linked Jak-Stat1 pathway. However, regulation of IFN- signaling is not fully understood, and not all responses to IFN- are Stat1 dependent. To identify novel elements involved in IFN- cell regulation, the cytoplasmic domain of the R2 subunit of the human IFN-R was used as bait in a yeast two-hybrid screen of a human monocyte cDNA library. This identified annexin A5 (AxV) as a putative IFN-R binding protein. The interaction was confirmed in pull-down experiments in which a GST-R2 cytoplasmic domain fusion protein was incubated with macrophage lysates. Furthermore, immunoprecipitation using anti-IFN-R2 Abs showed that AxV interacted with IFN-R2 to form a stable complex following incubation of cells with IFN-. In 293T cells with reduced expression of AxV, brought about by small interfering RNA targeting, activation of Jak2 and Stat1 in response to IFN- was enhanced. Inhibition of cell proliferation, a hallmark of the IFN- response, also was potentiated in HeLa cells treated with small interfering RNA directed at AxV. Taken together, these results suggest that through an inducible association with the R2 subunit of the IFN-R, AxV modulates cellular responses to IFN- by modulating signaling through the Jak-Stat1 pathway.

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