WITHDRAWN: Temperature-dependent IL6-STAT3-HSP90 signaling mediates viral entry

Abstract

IL6-STAT3 signaling is a canonical pro-inflammatory pathway that is evolutionarily conserved and plays important roles in both temperature stress and virus infection. However, our understanding of the molecular mechanisms underpinning the temperature-dependent pathogenesis of viral infection in ectotherms remains rudimentary. Here we report that Grass carp reovirus (GCRV) hijacks the temperature-dependent IL6-STAT3-HSP90 signaling axis to promote viral entry. Exploring the temperature-dependent phenotype of GCRV infection, we discovered that the activation of the IL6-STAT3 signaling facilitated viral entry by increasing the expression of heat shock proteins (HSPs). Further biochemical, transcriptomic, and microscopic analyses revealed that major capsid protein VP7 of GCRV interacted with HSP90 and relevant cytoskeleton proteins to enable viral entry. Accordingly, exogenous expression of either IL6, HSP90, or VP7 in cells engendered an increased viral entry in a dose dependent manner. Interestingly, other viruses infecting invertebrate insects, ectothermic vertebrates (e.g., fish, amphibians), and endothermic mammals (e.g., swine, mouse, human) have evolved similar mechanism to promote their infection. Altogether, our work delineates a pivotal role of the IL6-STAT3-HSP90 signaling axis in the temperature-dependency of viral entry, pinpointing the feasibility of developing targeted therapies for viral diseases in the future.