RLR signaling is amplified by reactive oxygen species and dysfunctions in autophagy (116.25)

Abstract

Abstract Infected cells utilize the RIG-I-like receptors (RLRs) to recognize the presence of RNA viruses in the cytosol. RLRs signal through IPS-1, which is localized to the mitochondrial membrane, resulting in the production of pro-inflammatory and antiviral cytokines. We are interested in the functional implications for the cellular localization of RLR signaling as it is clear that this is a point of intersect for important cellular processes and antiviral defense. We show that pro-inflammatory cytokine production in response to viral ligands is increased in several situations in the absence of autophagy due to increased levels of oxidative stress. The process of autophagy maintains the integrity of cellular organelles such as mitochondria and long-lived proteins by transporting them to the lysosomes for degradation. We have examined the role of defective autophagy and aging on cytosolic antiviral signaling using several ssRNA viruses as well as the dsRNA analog Poly I:C. We found that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling. We also present that RLR mediated cytokine production is increased in a human physiological condition that is known to involve decreased autophagy and increased oxidative stress.