Nanoscale Imaging Reveals that Caveolin-1 is Required for Spatial Organization of Interferon Receptor Molecules and Subsequent Innate Immune Response

Understanding spatial distribution and dynamics of receptors within unperturbed membranes is essential for elucidating their role in antiviral signaling, but conventional studies of detergent-resistant membrane fractions cannot provide this information. Caveolae are integral to numerous signaling pathways but their function in antiviral signaling is largely unexplored, apart from the finding that viruses exploit caveolae for entry into host cells. This study instead demonstrates a mechanism for virus evasion of host cell defenses through disruption of clusters of signaling molecules organized within caveolae. Super-resolution microscopy enabled the first single-molecule imaging of interactions between type I interferon receptors (IFN-R) and caveolae. Strikingly, knockdown of Caveolin-1, the protein that is the main component of caveolae, caused IFN-R clusters to disperse. Dispersal of IFN-R clusters led to a suppressed antiviral immune response through abrogation of downstream signaling, a response strongly suggesting that IFN-R organization within caveolae is critical for IFN-mediated antiviral defense.