Ro60—Roles in RNA Processing, Inflammation, and Rheumatic Autoimmune Diseases

Figure 1. Ro60/SSA2 domain structure and small RNA structural and functional surveillance for cellular distribution. (A) Ro60 comprises two major domains, vWFA and TROVE (1YVR and 1YVP). The TROVE domain is composed of toroid HEAT repeats. (B) Schematic representation of human Ro60 and other autoantigenic RBPs bound to small RNAs (such as YRNAs) and their nuclear–cytoplasmic transportation via XPO5/Ran GTPase [21]. (C) UNAfold predicted secondary structure of human YRNAs (hY1, hY3, hY4, and hY5). * designates conserved residues. (D) YRNA terminal stem 5′ and 3′ end sequences. Ro60 binds to the 5′-3′ stem-loop bulge, while La binds to the 3′ terminal uridine oligos. (E) Secondary structure of 5S rRNAs from bacteria, archaea, and eukaryotes (structures adapted from the 5S rRNA database: http://combio.pl/rrna/alignment/, Accessed on 16 May 2024). A designates the three-helix junction hinge region; C and D represent hairpin loops; B and D designate two internal loops; I–V designate helical stems.

Figure 2. Ro60’s role in ADAR-mediated RNA editing. (A) Post-transcriptional RNA editing: adenosine-to-inosine editing is catalysed by ADARs (ADAR1, 2, and 3) through hydrolytic deamination, in which ADARp150 is a sentinel of autoimmunity. (B) Ro60 serves as a regulator of RNA editing by mediating the structural surveillance of RNA moieties. In autoimmune diseases, due to the elevated expression of ADAR1p150 enzyme and retroelements L1 and Alu, structural surveillance by Ro60 is compromised, and excessive RNA editing occurs. Excessive RNA editing by ADARp150 in autoimmune diseases can be mutagenic, which may increase the risk of malignancy in patients with systemic autoimmune rheumatic disease.

Figure 3. Extracellular presentation and innate immune sensing of Ro60 RNP complex. (A) Donor cells can liberate Ro60 RNP complex in extracellular space via three basic mechanisms, small RNA-mediated translocation, extracellular vesicle-mediated translocation, and apoptotic body-mediated translocation. (B) The presentation of Ro60 RNP complex to myeloid APCs may promote endosomal TLR signalling and the production of pro-inflammatory cytokines and chemokines. (C) Ro60 RNP complex presentation to antigen-specific BCR and FcγRIIB, promoting endosomal TLR7 signalling, inflammation, and production of autoantibodies. IFNs can mount positive feedback on the transcription of IFN-stimulated genes. FcγRIIB regulates the activation of B cells. The loss or reduced expression of FcγRIIB is associated with an extrafollicular response and the production of autoantibodies.