Sort Your Self Out!

Abstract

Discrimination between viral and self-derived nucleic acid species is crucial in maintaining effective antiviral immunity whilst avoiding autoinflammation. Ahmad et al. and Chung et al. delineate the consequences of MDA5 gain of function and loss of ADAR1 activity, highlighting the blurring of the concept of self and non-self when considering endogenous retroelements.

Z-RNA biology: a central role in the innate immune response?

“…A bias for Z-RNA in SINEs and other repetitive elements could be advantageous for the cell, as SINEs represent a large source of endogenous dsRNA. Targeting proteins with Zα domains to these RNAs could ultimately help the cell better differentiate self- from non-self RNAs ( Uggenti and Crow 2018 ). Additionally, repeat elements may contain sequence biases which make them more prone to adopt Z-RNA as compared to other RNAs, such as the putative Z-Box (a sequence with pyrimidine-purine repeats) within Alu elements ( Herbert 2020 ).…”

Neurodegenerative diseases have genetic hallmarks of autoinflammatory disease

“…Notably, loss of function mutations in the RNA editing enzyme ADAR1 are a cause of Aicardi-Goutieres syndrome-a congenital disease that includes neurodegeneration as one of its symptoms, with affected newborns having the appearance of being subjected to in utero inflammatory injury (5,6). The absence of ADAR1 editing renders certain endogenous RNAs (including Alu element double-stranded RNAs) to be recognized as non-self by the pattern recognition receptor IFIH1 that then activates inflammation (76)(77)(78)(79)(80). Indeed, gain-of-function mutations in IFIH1 are also a cause of Aicardi-Goutieres syndrome, while deletion of IFIH1 rescues the phenotype caused by ADAR1 loss in mouse models (81).…”