Current Understanding of Circular RNAs in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a common and potentially fatal autoimmune disease that affects multiple organs. To date, its etiology and pathogenesis remains elusive. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs with covalently closed loop structure. Growing evidence has demonstrated that circRNAs may play an essential role in regulation of gene expression and transcription by acting as microRNA (miRNA) sponges, impacting cell survival and proliferation by interacting with RNA binding proteins (RBPs), and strengthening mRNA stability by forming RNA-protein complexes duplex structures. The expression patterns of circRNAs exhibit tissue-specific and pathogenesis-related manner. CircRNAs have implicated in the development of multiple autoimmune diseases, including SLE. In this review, we summarize the characteristics, biogenesis, and potential functions of circRNAs, its impact on immune responses and highlight current understanding of circRNAs in the pathogenesis of SLE.

Keywords: biological function; biomarker; circRNAs; endogenous regulation; systemic lupus erythematosus.

Figure 1

Biogenesis of three major types of circRNAs. (A) A linear mRNA is formed by canonical splicing from pre-messenger RNA (pre-mRNA). (B–E) CircRNAs are generated by backsplicing from pre-mRNA. (B) Lariat-driven circularization, exon-skipping leads to an exon-containing lariat whose restricted structure facilitates circularization. (C) Intro-pairing-driven circularization is mediated by base-pairing between inverted repeat elements such as ALU complementarity. (D) CiRNA biogenesis is mainly dependent on GU-rich motif and C-rich sequence. (E) RNA-binding proteins (RBP) serving as trans-acting factors can bring two splicing sites close together to promote circularization.

Figure 2

Functions of circRNAs. (A) CircRNAs can act as miRNA sponges to diminish the effects of miRNAs on target mRNAs. (B) CircRNAs can serve as scaffolds or decoys for RBPs to modulate their functions, thus affecting the related biological processes. (C) CircRNAs may be translated if they contain an internal ribosome entry site (IRES) or extensive N6-methyladenosines (m6A) modification. (D) CircRNAs can promote transcription by interacting with U1 small nuclear ribonucleoprotein (U1 snRNP) and the RNA polymerase II (Pol II) in the nucleus. (E) The processing of circRNAs could affect host gene expression by competing with their linear mRNA splicing.

Figure 3

Possible roles of circRNAs in SLE. CircRANs may be involved in the pathogenesis of SLE by regulating various biological processes, such as DNA methylation, activation of AKT signaling pathway, and aberrant PKR activation. Furthermore, circRNAs may serve as biomarkers for the diagnosis and severity of SLE.