Alu RNA Structural Features Modulate Immune Cell Activation and A-to-I Editing of Alu RNAs Is Diminished in Human Inflammatory Bowel Disease.

Thomas M Aune,Philip S Crooke,Krislyn P Porter,John T Tossberg,Rachel M Heinrich

doi:10.3389/fimmu.2022.818023

Thomas M Aune, Philip S Crooke + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2022.818023

Copy DOI

Abstract

Alu retrotransposons belong to the class of short interspersed nuclear elements (SINEs). Alu RNA is abundant in cells and its repetitive structure forms double-stranded RNAs (dsRNA) that activate dsRNA sensors and trigger innate immune responses with significant pathological consequences. Mechanisms to prevent innate immune activation include deamination of adenosines to inosines in dsRNAs, referred to as A-to-I editing, degradation of Alu RNAs by endoribonucleases, and sequestration of Alu RNAs by RNA binding proteins. We have previously demonstrated that widespread loss of Alu RNA A-to-I editing is associated with diverse human diseases including viral (COVID-19, influenza) and autoimmune diseases (multiple sclerosis). Here we demonstrate loss of A-to-I editing in leukocytes is also associated with inflammatory bowel diseases. Our structure-function analysis demonstrates that ability to activate innate immune responses resides in the left arm of Alu RNA, requires a 5’-PPP, RIG-I is the major Alu dsRNA sensor, and A-to-I editing disrupts both structure and function. Further, edited Alu RNAs inhibit activity of unedited Alu RNAs. Altering Alu RNA nucleotide sequence increases biological activity. Two classes of Alu RNAs exist, one class stimulates both IRF and NF-kB transcriptional activity and a second class only stimulates IRF transcriptional activity. Thus, Alu RNAs play important roles in human disease but may also have therapeutic potential.

Highlights

Alu elements belong to the class of short interspersed nuclear elements (SINEs), are unique to primates, and arose from a headto-tail fusion of 7SL RNA [1–3]
Severe influenza disease resulted in loss of A-to-I editing similar in magnitude to that observed in severe COVID-19 disease
We found an increase in expression levels of interferon-stimulated genes (ISGs) in Crohn’s disease (Cr) and ulcerative colitis (UC) compared to Celiac disease (Ce), irritable bowel disease (IBS), and healthy control (HC) (Figure 2G)

Summary

Introduction

Alu elements belong to the class of short interspersed nuclear elements (SINEs), are unique to primates, and arose from a headto-tail fusion of 7SL RNA [1–3]. The basic structure of an Alu element consists of a left arm and right arm of similar nucleotide sequence representing the two original 7SL RNA sequences joined by an A-rich linker. Alu elements contain two short promoter boxes both located in the left arm termed the 5’ A box and the 3’ B box that are involved in Alu replication and mobilization [6–8]. Rodents have a similar class of SINEs referred to as B1 elements that arose from a single 7SL RNA consisting only of the left arm [9]. Rodents contain additional SINE elements, referred to as B2, B3, and B4 classes, that arose from transfer RNAs

Methods

Results

Conclusion