Cellular & Molecular Immunology | 2019
Implications of m6A modification in autoimmune disorders
Abstract
N6-Methyladenosine (m6A) is the most common and abundant modification of RNA molecules, including mRNAs, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs). The m6A modification is catalyzed and dynamically regulated by recently discovered enzymes termed ‘writers” (methyltransferases including METTL3, METTL14, and WTAP), ‘erasers” (demethylases including FTO and ALKBH5) and ‘readers” (m6A-binding proteins including YTHDC1, YTHDC2, YTHDF1, YTHDF2, and YTHDF3). These modifications were recently shown to be involved in the regulation of different biological processes, including the inflammatory and antitumor immune responses, antiviral immunity and T-cell homeostasis. More recent studies have shown that aberrant m6A modifications are associated with various pathophysiologies, including autoimmune diseases. Autoimmune diseases (ADs) stem from the loss of immune tolerance to self-antigens and the involvement of specific organs, like type I diabetes mellitus, or multiple organs, like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren’s syndrome (pSS). ADs affect ~8% of individuals worldwide, making them a leading cause of morbidity and mortality, as observed by a steep rise in their annual incidence rate. Although the etiology of ADs is typically multifactorial, genetics and environmental factors play a critical role in the pathogenesis of ADs. Regulatory T cells (Tregs) are a specialized subpopulation of T cells that play a crucial role in suppressing the immune response, eventually leading to the maintenance of homeostasis and selftolerance. m6A mRNA methylation takes control of T-cell homeostasis by targeting the IL-7/STAT5/SOCS pathways and depleting Mettl3 in T cells, which disrupts naive T-cell homeostasis. Tong et al. have shown that Mettl3 depletion in Tregs enhances the mRNA stability of the SOCS gene, thereby blocking the transduction of cytokine signaling in the IL2-STAT5 pathway. These studies confirm the role of m6A modifications as a critical regulator of immune cell homeostasis and function, further suggesting that T cell-specific delivery of m6A-modifying agents is an effective treatment for various autoimmune diseases. More recently, Wang et al. reported the Mettl3-mediated m6A methylation of CD40, CD80, and Tirap (a TLR4 signaling adaptor) mRNA, which promoted dendritic cell (DC) activation and function. Additionally, Mettl3 depletion in DC impaired the phenotypic and functional maturation of DCs by decreasing expression of the costimulatory molecules CD40, CD80, and the cytokine IL-12, thereby reducing the ability of DCs to stimulate T-cell responses both in vitro and in vivo. Wang et al. have also shown that YTHDF1 recognizes m6A in CD40, CD80, and Tirap mRNA and promotes their protein translation (Fig. 1). A new finding from Wang et al. indicated that Mettl3-mediated m6A methylation of certain immune transcripts enhanced their translation in DCs by YTHDF1, thereby stimulating T-cell activation and strengthening TLR4/NFκB signaling-induced cytokine production. Very recently, Han et al. revealed that durable neoantigen-specific immunity was regulated by m6A-mediated methylation through YTHDF1. DCs are powerful antigen-presenting cells that induce antigenspecific T-cell responses. The dysregulation of DC-mediated immune activation and tolerance is closely associated with various pathological conditions. DC vaccination (DC therapy) employs DCs to activate the innate and adaptive immune system, which is a newly emerging and potent form of immune therapy used to treat cancer and other serious conditions. Mettl3, a positive regulator of DC function and TLR4 signaling, may have great relevance to the pathogenesis of diseases related to DC dysfunction and facilitate cancer immunotherapy, such as the adoptive infusion of DC vaccine or design of a potent cellular adjuvant. Recently, m6A was found to play important roles in inflammation and antiviral responses. Zong et al. showed that Mettl3 depletion decreased the m6A modification of Traf6 mRNA, resulting in the retention of its transcripts in the nucleus, followed by suppression of the NF-kB and MAPK signaling pathways. This event led to suppression of the inflammatory response, leading to the sustained absorption of long-chain fatty acids. Dental pulp inflammation is a typical inflammatory disease. A recent study demonstrated that in lipopolysaccharides (LPS)-treated human dental pulp cells, METTL3 expression and m6A modification levels were increased. Moreover, METTL3 depletion was shown to decrease the expression of LPS-induced inflammatory cytokines and suppress activation of the NF-kB and MAPK signaling pathways. This experimental evidence reveals the potential role of m6A RNA modification in the inflammatory response and provides clues on the molecular mechanisms associated with disease phenotypes. In addition, these cues can be used to develop new therapeutic strategies to treat inflammatory conditions. Zhang et al. recently reported that IFN–stimulated genes (ISGs) are essential effectors of the IFN-dependent antiviral immune response. Any change in ISG expression can cause dysfunctional antiviral responses and autoimmune disorders. Zhang et al. also provided substantial evidence that YTHDF3 inhibits the expression of ISGs through translational activation of the transcription corepressor forkhead box protein O3 (FOXO3). Rubio et al. recently discovered that type I interferon (IFN) production triggered by human cytomegalovirus (HCMV) is controlled by cellular METTL14 and ALKBH5. METTL14 depletion reduced virus reproduction and stimulated HCMV-induced IFNβ mRNA accumulation. However, ALKBH5 depletion had the opposite effect. ALKBH5 depletion and genome-wide transcriptome profiling