Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

y RNA microparticles produced in situ by rolling circle transcription, generating tandem repeat RNA strands (249) . Retrotransposons may also be able to activate both RIG-I and MDA5, as both can be activated by LINE1 RNA independently of DNA sensing mechanisms and retrotransposition (250) . Viral infections can also induce recognition of host RNAs. Herpes Simplex Virus 1 (HSV1) infection, for example, has been shown to induce translocation of the host pseudogene RNA5SP141 ribosomal RNA into the cytosol to bind to RIG-I. Knockdown of RNA5SP141 decreased cytokine signaling during infection with HSV and EBV as well as influenza A virus (IAV) (251) . RIG-I has also been found to be activated by hairpin RNA structures generated by cleavage of RNA by RNase L, which has been demonstrated to occur during HCV infection (179) as well as from mitochondrial dsRNA produced in p53 deficient mice (180) . The mitochondria, in particular, may be an important source of immunostimulatory host dsRNA. Viral infections are well-known to cause mitochondrial damage (252) . Knockdown and hepatocyte-specific conditional KO of mitochondrial RNA degrading enzymes resulted in the increase of cytoplasmic mitochondrial dsRNA which was able to activate MDA5 (253) . Additionally, extracellular vesicles (EV) secreted by apoptotic endothelial cells were found to contain long interspersed nuclear element (LINE) and short interspersed nuclear element (SINE) RNAs that are products of RNA polymerase III and were able to activate RIG-I signaling (254) . Collectively, these findings demonstrate the many unique ways by which cellular RNAs can modulate RIG-I and MDA5 functions as well as the potential implications of RIG-I activation by pharmaceuticals as an anti-viral or generalized immunotherapy, though much caution and studies would still be needed to determine the appropriate levels of RIG-I and MDA5 activation.