RNA sensing at the crossroads of autoimmunity and autoinflammation

Abstract

Immune-mediated diseases are common in humans. The immune system is a complex host defense system that evolved to protect us from pathogens, but also plays an important role in homeostatic processes, removing dead or senescent cells, and participating in tumor surveillance. The human immune system has two arms: the older innate immune system and the newer adaptive immune system. Sensing of foreign RNA is critical to the innate immune system's ability to recognize pathogens, especially viral infections. However, RNA sensors are also strongly implicated in autoimmune and autoinflammatory diseases, highlighting the importance of balancing pathogen recognition with tolerance to host RNAs that can resemble their viral counterparts. We describe how RNA sensors bind their ligands, how this binding is coupled to upregulation of type I interferon-stimulated genes, and the ways in which mutations in RNA sensors and genes that play important roles in RNA homeostasis have been linked to autoimmune and autoinflammatory diseases.

Keywords: RIG-I-like receptors; RNA sensors; Toll-like receptors; autoimmune disease; autoinflammatory disease; type I interferons.

FIGURE 1.

Viral RNA is sensed by pattern recognition receptors and results in transcriptional activation of type I interferon–stimulated genes (ISGs) and an antiviral response. Viruses enter cells by fusing with the plasma membrane or by endocytosis. After uncoating, viral RNA is exposed to the cell. Toll-like receptors recognize RNA in the endosome, and RIG-I-like receptors recognize RNA in the cytosol. They signal through adapter proteins to activate a pro-inflammatory signaling cascade and transcription of ISGs, including additional RNA sensors and genes that function in the antiviral response (e.g., IFITs, RNase L, PKR). (Image was created in BioRender.com.)

FIGURE 2.

Toll-like receptors and RIG-I-like receptors recognize different features of RNAs. (A) Toll-like receptors. TLR3 recognizes long double-stranded RNA and signals through the adapter TRIF. TLR7 recognizes single-stranded GU-rich RNA and binds guanosine at a second site. TLR8 recognizes short single-stranded GU-rich RNA and binds uridine at a second site. Both TLR7 and TLR8 signal through the cytosolic adapter MyD88. (B) RIG-I-like receptors sense dsRNA. RIG-I binds double-stranded sequences of at least 10 bp through its helicase domain. The C-terminal domain recognizes the RNA 5′-triphosphate moiety. RNA binding is coupled with derepression of the CARD signaling domains and CARD domain ubiquitination. The CARD domains bind to the adapter protein MAVS. MDA5 binds long double-stranded RNA and assembles into helical filaments along the RNA through its helicase and C-terminal domains. The CARD domains signal through MAVS. (Image was created in BioRender.com.)