The innate immune system acts as the first line of the host defenses, rapidly detecting and eliminating invading pathogens such as viruses, bacteria and fungi. Meanwhile, overproduction of pro-inflammatory cytokines potentially causes autoimmunity problems and diseases. Thus, the regulation of inflammatory responses must be controlled to ensure that host cells maintain proper immune homeostasis. The RIG-I receptor plays important roles in the cytosolic recognition of viral RNAs and in the regulation of the antiviral signaling pathway. However, the molecular mechanism of RIG-I-mediated antiviral signaling remains largely unknown.

The Qinmiao Sun lab at Institute of Zoology, Chinese Academy of Sciences, identified Syndecan-4 (SDC4) as a RIG-I-interacting factor in a yeast two-hybrid screen. They found that SDC4 expression is induced by viral infection, but it functions as a negative regulator that attenuates RIG-I activity, thereby maintaining antiviral signaling homeostasis in a feedback regulatory fashion. Mechanistically, they demonstrated that SDC4, via its carboxyl-terminal intracellular domain, interacts with RIG-I and CYLD, thereby facilitating the interaction between RIG-I and CYLD. This interaction increases the K63-linked deubiquitination of RIG-I, thereby attenuating RIG-I-mediated signal transduction, and it contributes to maintaining the homeostasis of innate immune signaling. This study establishes a novel regulatory mechanism by which SDC4 negatively regulates the type I IFN response to balance innate immunity and immune tolerance.

Dr. Dahua Chen’s and Hongmei Wang’s groups from Institute of Zoology, Chinese Academy of Sciences, also contributed to this study. This work has been published online in Nature Communications (http://www.nature.com/ncomms/2016/160609/ncomms11848/full/ncomms11848.html). This research was supported by grants from the National Basic Research Program of China and the National Natural Science Foundation of China.