Protein arginine methylation in viral infection and antiviral immunity

Keywords: Protein arginine methyltransferase, antiviral immunity, arginine methylation, post-translational modifications, viral infection.

Type I PRMT

Of the nine PRMTs, PRMT1 is the most abundant and potent enzyme, with both cytosolic and nuclear localization accounting for 85% of PRMT activity ²³. PRMT1 homodimerizes and selectively methylates RGG/RG motifs, which rely on two critical methionine residues (M48 and M155) that alter these amino acids, resulting in a marked change in substrate specificity and a reduction in catalytic activity ²⁴. Seven different isoforms of PRMT1 with distinct N-termini have been identified by alternative splicing, each with unique activity, substrate preference, and localization ²⁵. Interestingly, inhibition of PRMT1 causes a complementary elevation in PRMT5-mediated SDMA and MMA levels, which may result in opposite outcomes due to substrate scavenging ²¹. PRMT3 is predominantly cytosolic and has a unique N-terminal zinc finger domain that governs its substrate selectivity and catalytic activity by recruiting binding partners such as DAL-1/4.1B ^26,27. In contrast to PRMT1 and PRMT3, PRMT4/CARM1 mainly targets and methylates proline-rich sequences through its unique N-terminal EVH1 domain ²⁸. CARM1 also has a unique C-terminal transactivation domain that serves its transcriptional co-activator function. Both PRMT6 and PRMT8 are expressed in neurons, with PRMT6 predominantly localized in the nucleus, catalyzing arginine methylation of RGG/RG motifs ^29,30. Conversely, PRMT8 is anchored to the plasma membrane via N-terminal myristoylation and functions as a tetramer for substrate recognition and methylation ³¹.

Type II PRMT

Most of the SDMA formation catalyzed by type II enzymes is attributed to PRMT5, which forms a tight hetero-octameric complex with methylosome protein 50 (MEP50, also known as WD40 repeat-containing protein 77; WDR77) to selectively methylate substrates with GRG sequences ^20,32. The PRMT5:MEP50 complex also interacts with several substrate adaptors, such as pICln (chloride nucleotide-sensitive channel 1A), CoRP5 (cooperator of PRMT5), Menin, RioK1 (Rio kinase 1), and Piwi ³³. These partners mutually bind exclusively to the N-terminal domain of PRMT5 to determine the substrate choice and catalytic activity. PRMT9 is another type II enzyme with two SAM-binding and catalytic domains (an active site architecture similar to that of PRMT7) and forms a pseudodimer for substrate-binding and activity ^34,35. PRMT9 does not methylate arginine within RGG/RG motifs. Furthermore, only one of its substrates, spliceosome-associated protein 145, has been identified, implying that PRMT9 may play a regulatory role in alternative splicing ^35,36.

Type III PRMT

As the only type III enzyme, PRMT7 possesses a more confined substrate-binding cavity. The two conserved double E-loops are critical for its substrate preference, and mutations in these loops can cause PRMT7 to function as a type I or II enzyme ^34,37,38. PRMT7 predominantly methylates substrates with an RXR sequence, distinct from the preferences of type I and II enzymes ³⁹. Notably, nonfunctional mutations in the human PRMT7 gene have been reported, and both homozygous and heterozygous mutations have been linked to the short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) syndrome ⁴⁰.

Histone methylation by PRMTs

Histone arginine methylation is closely linked to transcriptional regulation, DNA damage repair, and chromatin reorganization ⁴². Although individual PRMTs may have preferences for different core histone substrates (H2A, H2B, H3, and H4), most arginine methylations imply the activation of gene expression (Figure 2 and Table 1). Notably, PRMT9 does not appear to methylate histones, and only a single histone catalytic site has been identified for PRMT2 and PRMT3 that maintains the expression of specific target genes. Alternatively, the dynamic crosstalk between different histone modifications, such as acetylation and methylation, serves as context-dependent histone markers that influence either active or repressive gene expression.

H4 methylation

H4 is mainly methylated at R3 by PRMT1, PRMT3, and PRMT5-8, which exert either positive or negative effects on gene transcription. For example, PRMT1 catalyzes H4R3me2a to epigenetically regulate the epithelial-to-mesenchymal transition process ⁶⁴ or to recruit the chromatin remodeling component SMARCA4 to upregulate genes involved in epidermal growth factor receptor signaling in colorectal cancer ⁶⁵. PRMT8 exhibits the highest homology with PRMT1 and demonstrates similar substrate activity in mediating H4R3 modifications ³¹. In addition, PRMT3- and PRMT6-mediated H4R3me2a promote the transcriptional activation of certain genes ^66,67. In contrast, PRMT5-mediated H4R3me2s have complex and context-dependent functions in gene expression via altered PRMT5 adaptor proteins. PRMT5 methylation of H4R3me2s can inhibit gene expression via DNA methylation or histone ubiquitination ⁶⁸. Conversely, similar to H3R8me2s, it can upregulate genes or be associated with H4K5 acetylation, serving as an active marker of expression ^58,69. Additionally, H4R3me2s modification by PRMT7 is belived to suppress gene expression by binding to gene promoters. This is associated with increased H4R3me2s levels and reduced H3K4me3, H3, and H4 acetylation ^70,71. Interestingly, PRMT7 also methylates H4 R17 and R19. H4R17me1 enhances PRMT5-mediated H4R3me2s, which, in turn, inhibits subsequent H3K4 methylation and H3K9 acetylation ^72,73. Therefore, different histone modifications, such as methylation and acetylation, cooperatively influence gene expression.

Non-histone methylation by PRMTs

In addition to histones, PRMTs target numerous substrates and interacting partners involved in transcriptional regulation, DNA repair, RNA processing, and cellular metabolism ^2,13,74. Over 4,000 proteins with arginine methylation at phosphosites have been documented ⁷⁵. These non-histone substrates include transcription factors, RNA splicing factors, binding proteins, and cellular signal transducers ⁷⁶. For example, RBPs are essential for RNA metabolism, such as splicing, maturation, translation. PRMTs recognize and methylate arginine residues within the RG/RGG-rich motifs of RBPs. This modification interferes with protein-protein and protein-nucleic acid interactions, thereby affecting RNA-associated processes ⁷⁷. In addition, proteome-wide analysis shows that numerous extensively arginine-methylated proteins are enriched in RNA splicing ²⁰. For example, PRMT5 methylates Sm proteins, a type of RBP, promoting the formation of spliceosomal small nuclear ribonuclear protein complexes ⁷⁸. It also methylates splicing factors to facilitate precise alternative splicing ⁷⁹. Additionally, PRMTs methylate proteins from multiple layers of the DNA damage response, such as BRCA1 (Breast cancer susceptibility gene 1), 53BP1 (p53 binding protein 1), and MRE11 (meiotic recombination 11), regulating their transcription, stability, activity, subcellular location, and protein or nucleic acid interactions to adapt to genotoxic stimuli ^80-82. Furthermore, PRMT-mediated arginine methylation has been implicated in several diseases, including cancer, neurodegenerative disorders, and inflammatory diseases, because of the wide range of functional substrates and biological processes involved ^13,14. Extensive research has been conducted on the potential regulatory functions of PRMTs in these diseases, offering promising therapeutic avenues, the details of which are not discussed herein.

Table 2.

Activity regulation of PRMTs by PTMs.

Regulation of PRMT1

PRMT1 activity and stability are subject to regulation through phosphorylation and ubiquitination (Figure 3). Under various stress stimuli, different upstream kinases phosphorylate PRMT1 and regulate its translocation and methyltransferase activity to control specific substrate methylation and signaling pathways. For instance, upon amino acid stimulation, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote its transportation to lysosomes in the cytoplasm for the methylation of WDR24 and subsequently activates the mTORC1 pathway, leading to tumor growth ⁸³ (Figure 3A). In response to genotoxic stress induced by cisplatin, DNA-dependent protein kinase (DNA-PK) phosphorylates and recruits PRMT1 to promote H4R3me2s methylation, resulting in the senescence-associated secretory phenotype ⁸⁴ (Figure 3B). During the self-renewing process of the epidermis, casein kinase 1α (CSNK1a1) phosphorylates PRMT1 at S248/T285/S289, regulating its chromatin localization and influencing the expression of target genes involved in maintaining self-renewal ⁸⁵. Additionally, PRMT1 represses the expression of grainyhead-like transcription factor 3 (GRHL3), a pro-differentiation transcriptional activator, ultimately inhibiting the terminal differentiation of progenitors ⁸⁵ (Figure 3C). In contrast, Unc51-like kinase 3 (ULK3) interacts with and phosphorylates PRMT1 to enhance its methyltransferase activity and promote chromatin recruitment. This, in turn, increases H4R3 methylation and cell proliferation, leading to the tumorigenic differentiation of epidermal keratinocytes, ultimately facilitating epidermal oncogenesis ⁸⁶ (Figure 3D). Notably, PRMT1 phosphorylation at Y291 impairs its ability to methylate substrates, resulting in altered substrate specificity and protein interactions ⁸⁷. In addition to phosphorylation, two E3 ubiquitin ligases, CHIP (carboxy-terminus of Hsc70 interacting protein) and E4B (ubiquitination factor E4B), recognize and ubiquitinate PRMT1 for proteasomal degradation ⁸⁸. Furthermore, Tripartite motif 48 (TRIM48) is another E3 ubiquitin ligase that promotes K48-linked polyubiquitination of PRMT1, leading to its proteasomal degradation. This process activates apoptosis signal-regulating kinase 1 (ASK1) and, under oxidative stress, induces cell death ⁸⁹. PRMT1-mediated methylation promotes the binding of ASK1 to its negative regulator thioredoxin (Trx), thereby inactivating ASK1 to ensure cell survival. In contrast, PRMT1 ubiquitination by TRIM48 prevents the ASK1-Trx interaction and facilitates ASK1 autophosphorylation, thereby suppressing cancer cell growth (Figure 3E). Additionally, USP11 deubiquitylates PRMT1 to regulate its interaction with the DNA repair protein MRE11, thereby controlling DNA damage repair ⁹⁰.

Regulation of CARM1

Similar to PRMT1, CARM1 can be phosphorylated to regulate its activity, stability, and co-activator function in a positive or negative manner (Figure 4). Specifically, phosphorylation of CARM1 at S217 by unknown kinase(s) blocks the binding of SAM to the catalytic site, whereas phosphorylation at S228, possibly by protein kinase C (PKC), disrupts CARM1's dimerization, ultimately restricting its methyltransferase activity during mitosis or dendritic maturation ^91-93. Phosphorylation of S448 by protein kinase A (PKA) promotes CARM1 binding to the estrogen receptor α (ERα), acting as a cofactor for ERα-responsive gene transcription and breast carcinogenesis ⁹⁴. In addition, phosphorylation of T132 by glycogen synthase kinase 3β (GSK-3β) prevents its ubiquitination and subsequent proteasomal degradation, thereby restoring lung epithelial cell migration that has been impaired by oxidative stress ⁹⁵. Specifically, the stability of CARM1 is controlled by polyubiquitination at K471 mediated by SCF E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2) ⁹⁶. Under nutrient-rich conditions, SKP2 actively catalyzes the ubiquitination and degradation of CARM1 in the nucleus. Conversely, under nutrient-starved conditions, SKP2 expression is transcriptionally suppressed by the phosphorylation of forkhead box O3a (FOXO3a) by AMP-activated protein kinase. This leads to increased levels of CARM1-mediated H3R17me2 and induces autophagy. In addition to phosphorylation, approximately 50% of CARM1 is modified by O-GlcNAcylation at S595, S598, T601, and T603. This modification plays a role in determining CARM1's substrate specificity ^97,98 and implicates O-GlcNAcylated CARM1 as a sensor of metabolic status and cellular stress. Moreover, CARM1 is automethylated at R550 (R551 in mouse) in exon 15. Such automethylation does not affect its enzymatic activity but rather alters ERα transcription and alternative mRNA splicing ⁹⁹. Alternative splicing of CARM1 mRNA generates two isoforms: full-length CARM1 (automethylated) and exon 15 deleted CARM1ΔE15 (automethylation-defective). These isoforms display differential distribution in stromal and epithelial cells, as well as different substrate methylation activity ¹⁰⁰. In addition, the stromal-predominant CARM1ΔE15 isoform loses its co-activator function in regulating ERα transcription, suggesting distinct roles for ERα in epithelial and stromal tissues ¹⁰⁰.

Regulation of PRMT5

Several upstream kinases regulate the phosphorylation of PRMT5 to achieve specific biological functions in response to various stresses, particularly during carcinogenesis (Figure 5). For instance, PKCι phosphorylates PRMT5 at S15 to enhance its methyltransferase activity upon interleukin-1β stimulation. This phosphorylation activates nuclear factor kappa B (NF-κB) through methylation of the p65 subunit at R30, ultimately promoting the growth of colorectal cancer cells ¹⁰¹. In ERα-positive breast cancer, liver kinase B1 (LKB1) interacts with and phosphorylates PRMT5 at T132, T139, and T144 within the nucleus. This phosphorylation event enhances its enzymatic activity and its binding to major co-activators such as MEP50, substrate partner pICln, and RioK1. These interactions determine PRMT5's enzymatic activity toward Sm proteins and histones ¹⁰². PRMT5 can be phosphorylated at Y297, Y304, and Y307, inhibiting its activity by Janus kinase 2 (JAK2) mutant JAK2V617F, a constitutively active form of JAK2. This disturbed interaction between PRMT5 and MEP50 serves as a plausible molecular mechanism for myeloproliferative neoplasms ¹⁰³. Furthermore, in response to normal physiological DNA damage, Src kinase phosphorylates PRMT5 at Y324, blocking its binding to SAM and impairing its methylation of 53BP1, consequently affecting non-homologous end-joining repair and triggering apoptotic cell death ⁸². PRMT5-mediated histone H4R3me2s methylation is also regulated by phosphorylation. For instance, ULK3 phosphorylates PRMT5, in addition to PRMT1, to enhance its recruitment to chromatin and H4R3me2s methylation, thereby preventing oncogenesis and tumorigenic differentiation of keratinocytes ⁸⁶. In contrast, RhoA activating kinase (ROK) phosphorylates PRMT5 at T80 enhancing its activity on H4R3me2s and activating proto-oncogenes, contributing to tumor formation in hepatocellular carcinoma. This effect is counteracted by myosin phosphatase (MP)-mediated dephosphorylation at T80 ¹⁰⁴. Alternatively, in tumor cells, MP is phosphorylated at T850 by ROK, and its diphosphatase activity on PRMT5 is inhibited, leading to the hyperphosphorylation of PRMT5 and increased H4R3me2s. Furthermore, the subcellular location and substrate specificity of PRMT5 are determined by C-terminal phosphorylation. Phosphorylation of T364 by Akt or SGK results in plasma membrane association and binding of PRMT5 to 14-3-3 proteins. Conversely, unphosphorylated PRMT5 binds to proteins containing PDZ domains ¹⁰⁵. This phosphorylation event acts as a PDZ/14-3-3 interaction switch, and further studies are required to explore its biological significance.

In addition to phosphorylation, the ubiquitination of PRMT5 affects its stability and methyltransferase activity. The E3 ubiquitin ligase CHIP catalyzes K48-linked polyubiquitination of PRMT5 and its subsequent proteasomal degradation to adapt to cellular stress in prostate cancer cells ¹⁰⁶. In contrast, TNF receptor-associated factor 6 (TRAF6), another E3 ubiquitin ligase, promotes K63-linked polyubiquitination of PRMT5, enhancing its methyltransferase activity on histone H4R3 and breast cancer cell proliferation ¹⁰⁷. Interestingly, PRMT5 activity is also regulated by methylation. However, unlike CARM1, which requires auto-arginine methylation ^99,100, PRMT5 is methylated by CARM1 at R505 ¹⁰⁸. Such methylation enhances methyltransferase activity and histone H4R3me2s enrichment at the promoter of the γ-globin gene or other genes, ultimately resulting in silenced gene expression. This indicates a critical role for PRMT5 methylation in the pathogenesis of hemoglobinopathies and cancer.

Regulation of other PRMTs

In addition to the aforementioned PRMTs, phosphorylation plays a role in regulating the activities of PRMT3 and PRMT6, each with different biological functions. PRMT3's catalytic activity and substrate-binding, particularly RPS2, require phosphorylation at Y87, the inhibition of which results in RNA maturation defects ¹⁰⁹. In the case of PRMT6, phosphorylation at S11 and T21 by casein kinase 2α (CK2α) inhibits its ubiquitination and proteasomal degradation and increases its binding and subsequent methylation of ribosomal chromatin condensation 1 (RCC1), facilitating RCC1 chromatin recruitment. This, in turn, promotes abnormal proliferation, radiation resistance, and tumorigenicity of glioblastoma stem cells ¹¹⁰. Moreover, similar to arginine methyltransferases, the activities of PRMT6, PRMT7, and PRMT8 undergo automethylation, similar to CARM1. For instance, automethylation of PRMT6 at R35 is essential for its stability and antiretroviral activity ^30,111. In contrast, PRMT8 automethylation at R58 and R73 inhibits its enzymatic activity by blocking the binding of SAM to the catalytic site ^112,113. However, the biological significance of PRMT7 automethylation is intricate, as several amino acids, including R32, R177, R363, R378, R387, R458, and R531, undergo automethylation ¹¹⁴. Notably, automethylation at R531 increases H4R3me1 levels in genes involved in the epithelial-mesenchymal transition, thereby promoting the progression and metastasis of breast cancer cells ¹¹⁵. Additionally, automethylation at R32 relieves the suppressive function of PRMT7 on the activation of mitochondrial antiviral signaling protein (MAVS) and subsequent antiviral innate immunity (more details are discussed below) ¹¹⁴. Future studies should investigate whether other PRMTs, such as PRMT1, PRMT2, and PRMT3, also undergo automethylation to alter their activity and substrate specificity.

Table 3.

PRMTs regulate viral infection.

PRMTs in dsDNA virus infection

PRMTs in dsRNA virus infection

PRMTs in (+)ssRNA virus infection

PRMTs in reverse transcribing virus infection

PRMTs regulate antiviral innate immunity

Increasing evidence suggests that PRMTs catalyze arginine methylation of host cellular proteins involved in antiviral immunity (Figure 8 and Table 4). Different PRRs recognize viral DNA or RNA to activate various transcription factors, such as IRF3, IRF7, and NF-kB, through various downstream signaling cascades, inducing the production of type I IFN and inflammatory factors ²⁰⁶. IFNs further induce the expression of IFN-stimulating factors (ISGs) and many antiviral proteins through the activation of the JAK-STAT signaling pathway to suppress viral infection and stimulate the immune cell-mediated antiviral response.

Cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, cGAMP) synthase (cGAS) is a key DNA recognition receptor that is activated by pathogenic DNA in the cytoplasm. It catalyzes the production of cGAMP, which promotes endoplasmic reticulum-Golgi translocation and dimerization of stimulator of interferon genes (STING) ²⁰⁷. Once activated, STING recruits and phosphorylates the TBK1-IRF3/NF-κB signaling pathway. In addition to its putative involvement in DNA virus sensing, cGAS/STING may also restrict RNA virus infection by recognizing abnormal extranuclear self-DNA released because of genomic DNA damage or mitochondrial stress caused by RNA virus infection ²⁰⁸. Interestingly, upon RNA virus (Sendai virus) and DNA virus (HSV-1) infection, PRMT1 forms oligomers to recruit and methylate the downstream effector TBK1 at R54, R134, and R228, promoting its aggregation and trans-autophosphorylation and the subsequent IRF3-mediated IFN-β production ²⁰⁹. Consistently, Prmt1 knockout mice show increased susceptibility to viral infections. Additionally, PRMT1 either binds to the intracytoplasmic domain of the IFN receptor or methylates STAT1 at R31, enhancing its DNA-binding activity and transcription factor function, thereby promoting the IFN-stimulated antiviral response ^210,211. In the absence of methylation caused by PRMT1 inhibition, phosphorylated STAT1 dimers exhibit an elevated association with the STAT inhibitor PIAS1 (a protein inhibitor of activated STAT 1), resulting in impaired STAT1-DNA-binding and IFN-I response ²¹¹. However, in tumor cells, PRMT1 negatively regulates cGAS activation by methylating cGAS at R133 in its N-terminus to prevent dimerization and suppress cGAS/STING signaling ²¹². Thus, PRMT1 exerts opposite effects on cGAS/STING signaling in different cell types and stressful environments. Higher expression and PRMT1-mediated cGAS methylation may, at least in part, contribute to suppressed basal levels of cGAS/STING signaling in tumors.

In addition to PRMT1, PRMT5 plays a complex regulatory function in the cGAS/STING signaling pathway (Figure 8). During DNA viral infection, PRMT5 negatively regulates the cGAS-mediated antiviral immune response by methylating cGAS at R124 within the RGG/RG motifs to block its DNA-binding activity ²¹³. However, in the case of RNA virus infections (e.g., VZV, SeV, Zika, and NDV), nuclear cGAS recruits and interacts with PRMT5 to demethylate histone arginine (H3R2me2s) of the IFN-β and IFN-α4 promoters. This facilitates chromatin accessibility of IRF3, ultimately boosting IFN-I expression ²¹⁴. The non-canonical anti-RNA viral function of cGAS is independent of its nucleotidyltransferase and DNA-binding activities, suggesting that cGAS acts as an antiviral cytosolic DNA sensor (DNA virus) or co-transcription factor (RNA virus). The conflicting roles of PRMT5 in cytoplasmic and nuclear cGAS may ensure the accurate duration and strength of IFN-I production. PRMT5 appears to interact with cytoplasmic cGAS, limiting its DNA-binding ability, thereby preventing abnormal inflammation caused by cytosolic self-DNA during stress ²¹⁵. Upon viral infection, PRMT5 dissociates from cytoplasmic cGAS and moves to the nucleus, where it directly activates cGAS/STING to mobilize antiviral actions (DNA viruses) or interacts with nuclear cGAS to prime innate immune responses (RNA viruses) ²¹⁴. In addition, PRMT5-mediated symmetric arginine methylation is required for PRR-dependent IFN production in undifferentiated monocytes and activated subsets of T lymphocytes ²¹⁶. PRMT5 conservatively controls IFN transcription by activating TBK1, c-Jun, and ATF2. PRMT5 also promotes IFN signaling by enhancing the phosphorylation of STAT1 in T cells during the pathogenesis of acute graft-versus-host disease ²¹⁷. However, the controversial role of PRMT5 in IFN-I production has also been demonstrated. PRMT5 represses the cGAS/STING pathway by methylating IFN-γ-inducible protein 16 (IFI16), another cellular DNA sensor that stimulates STING, at R124. This ultimately attenuates dsDNA-mediated activation of the TBK1-IRF3 signaling in melanoma tumors ²¹⁸. PRMT5 also transcriptionally inhibits the NLR family CARD domain-containing 5 (NLRC5) to regulate the antigen presentation pathway of MHC class I ²¹⁸. Thus, PRMT5 exerts paradoxical but rational physiological functions in diverse biological processes and in cells of distinct origins.

Following RNA virus infection, RNA recognition receptors, such as RIG-I, MDA5, and Toll-like receptors (TLRs), rapidly detect and bind viral RNA in the cytoplasm or endosomal compartments to initiate downstream signaling cascades. This initiation of downstream signaling cascades converges upon the activation of the TBK1-IRF3/7 and IKK-NF-kB axes, leading to IFN induction ^148,206. RIG-I and MDA5 transmit signals through MAVS, which is localized in the outer mitochondrial membrane. Meanwhile, TLRs recruit either TIR domain-containing adaptor inducing IFN-β (TRIF) adaptor protein or myeloid differentiation primary response 88 (MyD88) to transmit signals from viral infections. In response to an RNA viral infection, MAVS is activated to form prion-like aggregates via K63-linked polyubiquitination, which is mediated by the ubiquitin E3 ligase TRIM31 ²¹⁹. MAVS activity is also tightly regulated by PTMs to fine-tune IFN-I production, as inappropriate, persistent, or spontaneous aggregation of MAVS leads to systemic autoimmunity ²²⁰. PRMT9 has recently been identified as a negative MAVS regulator that methylates the R41 and R43 residues to prevent their aggregation and auto-activation during resting conditions (Figure 8) ²²¹. Upon viral infection, PRMT9 dissociates from the mitochondria, leading to MAVS activation and IFN-I stimulation. In addition, PRMT7 monomethylates MAVS at R52 to attenuate its binding to TRIM31 and subsequent TRIM31-mediated polyubiquitination, as well as its interaction with RIG-I. This results in the suppression of MAVS aggregation and activation of the RLR signaling pathway ¹¹⁴. Conversely, viral infection-induced automethylation of PRMT7 at R32 alleviates the suppression of MAVS activation and promotes its interaction with the MAVS-recruited ubiquitin E3 ligase SMURF1, leading to K48-linked polyubiquitination and proteasomal degradation of PRMT7 ¹¹⁴. Thus, decreased MAVS methylation facilitates aggregate formation and activation of the innate antiviral response.

Furthermore, following viral infection, PRMT6 interacts with and sequesters IRF3 independently of its methyltransferase activity. Consequently, the interaction between TBK1 and TRF3 is disrupted, leading to the suppression of IRF3-mediated IFN-I production ²²². In zebrafish, PRMT3 interacts with RIG-I to inhibit its activation and subsequent IRF3 phosphorylation, thereby negatively regulating antiviral responses to spring viremia of the carp virus (SVCV) and grass carp reovirus (GCRV) infection ²²³. Additionally, PRMT2 binds and methylates TRAF6 at R100 within the C-terminus, preventing its K63-linked auto-ubiquitination and activation of the downstream TBK1/IKKε signaling pathway ²²⁴. The N-terminal of PRMT2 also competes with MAVS for TRAF6 binding and disrupts the recruitment of TBK1/IKKε to MAVS. Thus, PRMT6 has a bidirectional impact, negatively regulating antiviral innate immunity against SVCV and GCRV infections.

Apart from viral infection, PRMT-mediated arginine methylation also enhances IFN-β production in the TLR4/IRF3 signaling pathway ²²⁵. Following LPS stimulation, PRMT1-3 have been shown to methylate TLR4 and IRF3, with PRMT2 having the most prominent impact (Figure 8). PRMT2 can either methylate TLR4 at R731 and R812, or IRF3 at R285, and methylated TLR4 at R812 directly binds to methylated IRF3. IRF3 methylation also induces its dimerization and promotes nuclear import, resulting in increased IFN-β production ²²⁵. Furthermore, the methylation of TLR4 by PRMT1 or PRMT2 increases IRF3 transcriptional activity, irrespective of LPS stimulation. Further investigation is needed to determine whether PRMT2-mediated TLR4 methylation augments antiviral innate responses via other downstream effectors, such as the MyD88-dependent signaling pathway.

Finally, several PRMTs positively regulate NF-kB signaling and target gene expression in response to different stresses. For instance, CARM1 acts as a promoter-specific transcriptional co-activator of NF-kB that interacts with p300 and the NF-kB subunit p65, augmenting the recruitment of NF-kB to the chromatin of specific genes ²²⁶. PRMT1 forms a complex with poly (ADP-ribose) polymerase 1 and directly interacts with the NF-kB subunit p65 to co-activate NF-kB-dependent gene expression synergistically with CARM1 ²²⁷. In addition, upon TNF-α stimulation, PRMT6 promotes p65 nuclear shuttling and interacts with p65 at selective NF-κB target promoters as a co-activator, enhancing gene expression ²²⁸. Furthermore, PRMT5 directly interacts with and dimethylates p65 at R30, thereby promoting gene expression ²²⁹. Given that the methyltransferase activity of PRMT1 and CARM1 is essential for their co-activator function, further research is required to investigate whether PRMT1 and CARM1, similar to PRMT5, directly methylate p65 to activate NF-κB. In contrast, PRMT2 inhibits NF-κB-dependent transcription by preventing the nuclear export of IκB-α. This leads to the nuclear accumulation of IκB-α, which curbs NF-κB DNA- binding and the expression of genes targeted by NF-κB ²³⁰. However, it remains to be determined whether PRMTs-mediated regulation of NF-κB has a potential role in the antiviral innate immune response.

PRMTs as emerging antiviral targets

Given the pivotal roles of PRMTs in viral infections and antiviral innate immune responses, PRMTs are emerging as potential therapeutic antiviral targets. However, in vitro studies have identified a limited number of PRMT inhibitors as potent antiviral agents. This could be attributed to the lack of specific PRMT inhibitors available for exploring the virus-associated functions of PRMTs. For instance, a type I PRMT inhibitor (MS0233) and PRMT5-specific inhibitor (GSK3326595) have been shown to inhibit SARS-CoV-2 replication ¹⁵⁴. IBDV replication is also impaired by the PRMT5 inhibitor HLCL-61 ¹⁴⁶. General PRMT inhibitors (AdOx and AdoHcy) efficiently inhibit HSV-1 replication ¹²⁴. In zebrafish, the PRMT3 inhibitor SGC707 has been found to effectively inhibit SVCV and GCRV infections ²²³. Furthermore, the CARM1 specific inhibitor 7 g (1-benzyl-3,5-bis-(3-bromo-4-hydroxy-benzylidene) piperidin-4-one) effectively reverses HIV latency and facilitates reactivation ¹⁸⁶. This suggests that 7 g may serve as a novel latency-disrupting compound and presents a possible combinatorial strategy for eliminating the latent HIV provirus reservoir. To date, several potent PRMT inhibitors with different structural scaffolds have been developed for cancer therapy. Some of these inhibitors, such as the PRMT1 inhibitor GSK3368715 and PRMT5 inhibitors PF-06939999, GSK3326595, and JNJ-64619178, have been investigated in clinical trials ²³¹. Additional studies are required to examine the antiviral properties of these compounds.

Funding

This work was supported by the National Natural Science Foundation of China (82372244, 82373917), and the Basic and Applied Basic Research Foundation of Guangdong Province (2021B1515120088). We would like to thank Editage (www.editage.cn) for English language editing.

Author contributions

KZ conceptualized, wrote and finalized the manuscript. SC, ZR and YW took part in authoritative discussions and gave revision of the manuscript. All authors read and approved the final manuscript.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Data Availability Statement

All data generated or analyzed during this study are included in this published article.