Alternatively Spliced Soluble Coxsackie-adenovirus Receptors Inhibit Coxsackievirus Infection

Abstract

The coxsackie-adenovirus receptor (CAR) is a transmembrane receptor of the immunoglobulin superfamily whose expression is altered in myocardial and malignant diseases. Soluble isoforms of other adhesion molecules and cytokine receptors have been proven to have significant agonist and antagonist effects on their full-length receptors; however, little is known about soluble CAR receptors. Using reverse transcription-PCR, we identified three CAR isoforms that lack the transmembrane domain and are the result of alternative RNA splicing events between exons IV and VII (CAR4/7), exons III and VII (CAR3/7), and exons II and VII (CAR2/7). The three CAR isoforms contain different regions of the extracellular domain of CAR and have C termini that are distinct from the full-length receptors. These alternatively spliced CAR proteins are released from transfected HeLa cells confirming that they are soluble proteins. In addition, the soluble CAR proteins are able to interact with the bacterially expressed extracellular domain of CAR. In addition, CAR4/7 but not CAR2/7 was found to bind to coxsackievirus B3 (CVB3). Each of the three soluble CAR isoforms is able to inhibit CVB3 infection of transfected HeLa cells. Given that soluble CAR isoforms can bind to the extracellular domain of CAR and the CVB3 capsid, they may have significant inhibitory or stimulatory effects on CAR signaling and may have an important role in the host defense against viral infection.