RBP-RNA interactions in the control of autoimmunity and autoinflammation

Abstract

Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and autoinflammatory diseases. RNA-binding proteins (RBPs) are essential for immune cell development and function, mainly via exerting post-transcriptional regulation of RNA metabolism and function. Functional dysregulation of RBPs and abnormities in RNA metabolism are closely associated with multiple autoimmune or autoinflammatory disorders. Distinct RBPs play critical roles in aberrant autoreactive inflammatory responses via orchestrating a complex regulatory network consisting of DNAs, RNAs and proteins within immune cells. In-depth characterizations of RBP-RNA interactomes during autoimmunity and autoinflammation will lead to a better understanding of autoimmune pathogenesis and facilitate the development of effective therapeutic strategies. In this review, we summarize and discuss the functions of RBP-RNA interactions in controlling aberrant autoimmune inflammation and their potential as biomarkers and therapeutic targets.

Fig. 1. RBP-mediated regulation of immune responses in autoimmunity and autoinflammation.

Immunity and inflammation are tightly controlled by regulatory networks, including epigenetic, metabolic and immunological factors. Abnormal activation of PRRs-triggered innate immunity leads to aberrant production of proinflammatory cytokines and type I IFNs, and activation of innate immune cells. The subsequent dysregulations of T cell- and B cell-dependent adaptive immunity play important roles in the breakdown of self-tolerance and the development of autoimmune pathology. RBPs are critical for mediating multi-level regulation of immune responses during autoimmunity and autoinflammation. RBPs are shown in yellow boxes next to immune responses that they target. RBPs that activate inflammatory responses or promote autoimmune pathogenesis are shown in red and those that inhibit inflammatory responses or limit autoimmune pathogenesis are shown in green. ADAR1 adenosine deaminase acting on RNA 1, SKIV2L superkiller viralicidic activity 2-like, hnRNP M heterogeneous nuclear ribonucleoprotein M, hnRNP UL1 heterogeneous nuclear ribonucleoprotein UL1, TTP tristetraprolin, HuR human antigen R, TIA-1 T-cell restricted intracellular antigen-1, hnRNP A2B1 heterogeneous nuclear ribonucleoprotein A2B1, G3BP1 GTPase-activating protein SH3 domain-binding protein 1, Arid5a AT-rich interactive domain-containing protein 5a, Mettl3 methyltransferase like 3, SRSF1 serine and arginine-rich splicing factor 1, ZFP36L1 zinc finger protein 36, C3H type-like 1, PTBP1 polypyrimidine tract binding protein 1, PRRs pattern recognition receptors, IFN interferon, IL interleukin, TNF tumor necrosis factor, Teff effector T cells, Treg regulatory T cells, Tfh follicular T helper cells, Tfr follicular regulatory T cells.

Fig. 2. Control of RNA metabolism and function by RBPs in innate immune response during autoimmunity and autoinflammation.

RBPs regulate the activation of PRR-triggered innate immunity via targeting various steps at transcriptional, post-transcriptional or translational levels. a FBL mediates 2′-O-methylation of RNA and prevents the innate recognition by MDA5 and IFN responses. ZBP1 recognizes self Z-RNA to promote pathologic inflammation. b ADAR1 mediates RNA A-to-I editing, thus allowing effective antiviral immunity while preventing pathogenic autoinflammation. c The SKIV2L subunit of the RNA exosome cleaves self RNA produced by the endonuclease IRE-1, and thereby inhibits RIG-I activation and type I IFN-dependent autoinflammation. d G3BP1 enhances DNA binding of cGAS and cGAS-dependent IFN production. hnRNP A2B1 recognizes viral DNA and enhances cGAS/STING-dependent IFN response. e The short isoform of MyD88 (MyD88s) inhibits TLR-triggered inflammation due to its failure to recruit IRAK-4. SF3a and SF3b mRNA splicing complexes reduce the MyD88s mRNA levels. f lncRNA-ISIR binds to IRF3 and impedes the inhibitory effect of Fli-1, thus enhancing IRF3 activation, IFN response and autoinflammation. g TET2 promotes the degradation of SOCS3 mRNA through ADAR1, facilitating cytokine-induced emergency myelopoiesis and mast cell expansion and activation during pathogen infection. h hnRNP UL1 inhibits NF-κB-mediated inflammation via competing with NF-κB to bind κB sites, while hnRNP UL1 expression decreases in RA patients. i hnRNP M inhibits pre-mRNA splicing and maturation of inflammatory transcripts such as IL-6 to negatively regulate inflammatory responses. j TTP and Regnase-1 destabilize mRNAs of proinflammatory cytokines such as IL-6 and TNF to control autoimmunity. k HuR downregulates mRNA translation to suppress aberrant inflammation and autoimmunity. l lnc-DC controls human DC differentiation and function via directly binding to STAT3 in the cytoplasm to prevent SHP1 binding and promote STAT3 phosphorylation. m Mettl3 mediates m⁶A methylation of transcripts of co-stimulatory molecules CD40, CD80 and TLR4 signaling adaptor TIRAP to enhance their translation in DCs, stimulating T cell activation and strengthening TLR4/NF-κB signaling-induced cytokine production. n CCR7 ligation upregulates expression of lnc-Dpf3 via relieving m⁶A-dependent degradation, consequently leading to inhibition of HIF1α-dependent glycolysis and DC migration. RBPs responsible for each step are shown in red ovals. FBL fibrillarin, ZBP1 Z-DNA-binding protein 1, MDA5 melanoma differentiation-associated gene 5, ADAR1 adenosine deaminase acting on RNA 1, RIG-I retinoic acid-inducible gene I, SKIV2L superkiller viralicidic activity 2-like, G3BP1 GTPase-activating protein SH3 domain-binding protein 1, cGAS cyclic GMP AMP synthase, hnRNA A2B1 heterogeneous nuclear ribonucleoprotein A2B1, MyD88 Myeloid differentiation primary response gene 88, SF3a/3b splicing factor 3a/3b, IRF3 interferon regulatory factor 3, Fli-1 flightless-1, TET2 ten-eleven translocation 2, hnRNP UL1 heterogeneous nuclear ribonucleoprotein UL1, hnRNP M heterogeneous nuclear ribonucleoprotein M, TTP tristetraprolin, HuR human antigen R, Arid5a AT-rich interactive domain-containing protein 5a, ARE adenine uridine (AU)-rich elements, DC dendritic cells, STAT3 signal transducer and activator of transcription 3, SHP1 Src-homology 2 (SH2) domain-containing phosphatase 1, Mettl3 methyltransferase like 3, YTHDF1/2 YTH domain-containing protein 1/2, HIF1α hypoxia-inducible factor-1 alpha.

Fig. 3. Control of RNA metabolism and function by RBPs in adaptive immune response during autoimmunity and autoinflammation.

RBPs regulate the Th cell differentiation, Treg cell function and B cell activation during development of AIDs via multiple mechanisms. Upper: RBP regulation of Th17 and Tfh cell differentiation. TTP, Regnase-1 and Roquin negatively regulate a set of Th17-related genes such as OX40 via mRNA decay to inhibit Th17 cell differentiation. Regnase-1 and Roquin repress the expression of ICOS and OX40 mRNAs via post-transcriptional regulation to inhibit Tfh cell differentiation. Middle: RBP regulation of Treg cell generation and function. ZFP36L2 decreases Helios expression in Foxp3⁺ Tregs via directly binding to the 3′ UTR of Helios mRNA and destabilizing it, leading to inhibition of iTreg function. Mettl3 mediates m⁶A modification of SOCS mRNA to maintain Treg cell generation and immune tolerance. Roquin upregulates PTEN mRNA expression through antagonizing miR-17–92 binding to PTEN mRNA, and thus suppresses the conversion of Treg to Tfr cells. Bottom: RBP regulation of B cell activation and germinal cell (GC) responses. ZPF36L1 post-transcriptionally limits mRNA levels of transcription factors KLF2 and IRF8 to promote GC response. PTBP1 promotes B cell proliferation and activation in GC via controlling alternative splicing of transcripts of c-Myc target genes such as Pkm and Tyms. lncRNA XIST interacts with TRIM28 to maintain X-inactivation and inhibit X-linked TLR7 gene expression, contributing to restraining of atypical B cell formation. RBPs responsible for each of these steps are shown in red ovals. APC antigen-presenting cells, Th17 IL-17-expressing T cells, Tfh follicular T helper cells, Treg regulatory T cells, iTreg inducible regulatory T cells, Tfr follicular regulatory T cells, TTP tristetraprolin, HuR human antigen R, Arid5a AT-rich interactive domain-containing protein 5a, STAT3 signal transducer and activator of transcription 3, IL-17 interleukin 17, ICOS inducible T cell costimulator, ARE adenine uridine (AU)-rich elements, ZFP36L2 zinc finger protein 36, C3H type-like 2, Ikzf2 IKAROS Family Zinc Finger 2, Mettl3 methyltransferase like 3, SOCS suppressor of cytokine signaling protein, PTEN phosphatase and tensin homolog, ZPF36L1 zinc finger protein 36, C3H type-like 1, IRF8 interferon regulatory factor 8, KLF2 kruppel like factor 2, MZ marginal zone, PTBP1 polypyrimidine tract binding protein 1, Pkm Pyruvate Kinase M, Tyms thymidylate synthetase, TRIM28 tripartite motif containing 28.