Understanding the epitranscriptional rules of escaping detrimental innate immune activation
Lead Research Organisation:
Newcastle University
Department Name: Biosciences Institute
Abstract
Our cells have evolved special sensors (RLR-signalling) to rapidly mount a protective, immunological response to the presence of long, perfectly paired double-stranded RNAs (dsRNAs), indicative of viral invasion. Intriguingly, our cells have the "blueprints" for generating such dsRNAs (e.g Alu-repeats for humans and SINEs/LINEs-repeats for mice), but these apparently escape cytoplasmic sensing. Studies suggest that adenosine deaminase acting on RNA-1 (ADAR1) grants immunosuppressive properties to our dsRNAs by converting adenosines to inosines (i.e A-to-I RNA-editing) (Science.2015;349(6252):1115-20). Despite the requirement of ADAR1-mediated epitranscriptomic changes for life, it remains a mystery how exactly these suppress the endogenous dsRNA-sensing.
We demonstrated that ADAR1 is highly expressed in vascular endothelial cells(ECs) and edits Alu-dsRNAs, unwinding them into more linear structures (Nat Med.2016;22(10):1140-1150) due to unstable I:U pairs. ECs line the interior of blood vessels thus contributing to innate immunity in all organs and diseases. Our previous work has linked vascular ADAR1-induced Alu-dsRNA-editing to inflammatory and autoimmune diseases (Nat Med.2016;22(10):1140-1150; J Autoimmun.2020;106:102329). We hypothesize that EC RNA-editing is particularly important for innate immunity and functions through impeding the deleterious accumulation of immunostimulatory-dsRNAs.
We demonstrated that ADAR1 is highly expressed in vascular endothelial cells(ECs) and edits Alu-dsRNAs, unwinding them into more linear structures (Nat Med.2016;22(10):1140-1150) due to unstable I:U pairs. ECs line the interior of blood vessels thus contributing to innate immunity in all organs and diseases. Our previous work has linked vascular ADAR1-induced Alu-dsRNA-editing to inflammatory and autoimmune diseases (Nat Med.2016;22(10):1140-1150; J Autoimmun.2020;106:102329). We hypothesize that EC RNA-editing is particularly important for innate immunity and functions through impeding the deleterious accumulation of immunostimulatory-dsRNAs.
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ORCID iD |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/T008695/1 | 01/10/2020 | 30/09/2028 | |||
2601373 | Studentship | BB/T008695/1 | 01/10/2021 | 30/09/2025 |