The Role of Protein Methyltransferases in Immunity

Abstract

The immune system protects our body from bacteria, viruses, and toxins and removes malignant cells. Activation of immune cells requires the onset of a network of important signaling proteins. Methylation of these proteins affects their structure and biological function. Under stimulation, T cells, B cells, and other immune cells undergo activation, development, proliferation, differentiation, and manufacture of cytokines and antibodies. Methyltransferases alter the above processes and lead to diverse outcomes depending on the degree and type of methylation. In the previous two decades, methyltransferases have been reported to mediate a great variety of immune stages. Elucidating the roles of methylation in immunity not only contributes to understanding the immune mechanism but is helpful in the development of new immunotherapeutic strategies. Hence, we review herein the studies on methylation in immunity, aiming to provide ideas for new approaches.

Keywords: arginine methylation; inflammation; lysine methylation; protein methylation.

Figure 1

Chemistry of arginine methylation. Type I protein arginine methyltransferases catalyze asymmetric methylation of arginine, whereas Type II protein arginine methyltransferases catalyze symmetric demethylation in arginine.

Figure 2

Characteristic domains of arginine protein methyltransferases. Arginine protein methyltransferases (PRMTs) share a common structural domain, the methyltransferase domain. Additionally, some members of PRMTs feature distinct structural domains, enhancing their functional diversity. These additional domains include Src-homology 3 (SH3), zinc-finger (Zn), nuclear translocation (NT), transactivation (TA), dimerization (Dimer), and tetratricopeptide repeat (TPR). The presence of these characteristic domains contributes to the unique roles and regulatory functions exhibited by different PRMTs.

Figure 3

Chemistry of lysine methylation. Lysine methyltransferases (KMTs) facilitate the addition of methyl groups to substrates. Typically, the lysine ε-amino groups can accommodate up to three methyl groups, leading to the formation of mono-, di-, or trimethyllysine.

Figure 4

Characteristic domains of lysine protein methyltransferases. Most lysine methyltransferase (KMT) families exhibit an evolutionarily conserved SET domain, except for the DOT1-like family. Additional domains include chromo shadow (chromo), plant homeodomain finger (PHD), zinc-finger (Zn), and Cys2–His2 zinc finger (C2H2) domains.

Figure 5

The canonical and non-canonical NF-κB signaling pathway. The canonical pathway is triggered by TLRs, TNFRs, and IL-1R, leading to the phosphorylation and degradation of the inhibitory protein IκB. NF-κB is activated by its release from the IκB-containing complex and translocates into the nucleus. The non-canonical pathway depends on the activation of p100/RelB complex by BAFFR, CD40, and RANK. This cascade involves the phosphorylation of NIK, which in turn phosphorylates IKKα. Subsequently, the p52-RelB heterodimer is activated and translocates to the nucleus.

Figure 6

Regulatory mechanisms of PRMT1 in inflammatory responses. PRMT1 plays a multifaceted role in cellular processes by directly binding to and methylating TRAF6. The arginine methylation of TRAF6 by PRMT1 downregulates its ubiquitin ligase activity, resulting in the suppression of basal NF-κB activation. PRMT1 also methylates RelA, regulating DNA affinity and the expression of NF-κB target genes. The interaction between PRMT1 and RelA activates NF-κB-dependent gene expression at the promoters of MIP2 and HIV. Furthermore, PRMT1 methylates PIAS1, influencing IFN transcription. Additionally, PRMT1 methylates STAT1 on Arg-31, and this methylation is essential for transcriptional activation.

Figure 7

Potential role of methylation on CD4⁺ cells. Methyltransferase like PRMT1, PRMT5, G9a, EHMT1, SETDB1, SMYDs, and EZH2 exert their influence on CD4⁺ T cells, impacting subsequent T cell differentiation and maturation. This, in turn, leads to alterations in the expression of inflammatory factors such as IFN and ILs.