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Protein arginine methylation in viral infection and antiviral immunity - PubMed

  • ️Sun Jan 01 2023

Review

. 2023 Oct 24;19(16):5292-5318.

doi: 10.7150/ijbs.89498. eCollection 2023.

Affiliations

Review

Protein arginine methylation in viral infection and antiviral immunity

Kai Zheng et al. Int J Biol Sci. 2023.

Abstract

Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.

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

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1

Arginine methylation and protein arginine methyltransferases (PRMTs). (A) Classification and structural domains of PRMTs. The S-adenosyl-L-methionine (SAM) binding and catalytic active domain consists of six conserved motifs. The preferences of the arginine motifs for the PRMTs are as follows: PRMT1, PRMT3, PRMT5 and PRMT6 preferentially methylate arginines within the arginine (R)-glycine (G) or RGG motif; PRMT7 has a preference for arginines within the RXR sequences; CARM1 selectively methylates arginines with neighboring proline, glycine and methionine (PGM). SH3, SH3 domain; Zn-F, zinc finger domain; TAD, transactivation domain; TPR, the tetratricopeptide repeat. (B) Arginine methylation by PRMTs. Type I, II and III enzymes initially transfer methyl group to the nitrogen atoms of the guanidino group to form monomethyl arginine (MMA), which is further catalyzed by type I enzymes to generate asymmetrical dimethyl arginine (ADMA), or by type II enzymes to form symmetrical dimethyl arginine (SDMA).

Figure 2
Figure 2

Histone arginine methylation by PRMTs. Key arginine (R) residues methylated by PRMTs on histone tails and their consequences for transcriptional regulation are illustrated. PRMT, protein arginine methyltransferases.

Figure 3
Figure 3

Regulation of PRMT1 by post-translational modifications. (A) PRMT1 is phosphorylated and activated by CDK5 to methylate WDR24, resulting in mTORC1 activation and tumorigenesis upon amino acid stimulation. (B) DNA damage caused by cisplatin triggers the binding of DNA-PK to PRMT1, which in turn phosphorylates PRMT1 and promotes the H4R3 methylation, leading to the senescence-associated secretory phenotype. (C and D) PRMT1 is phosphorylated by CSNK1a1 or ULK3 to epigenetically regulate the expression of genes involved in the epidermal self-renewal and oncogenesis via histone methylation. (E) PRMT1 is either ubiquitinated by E4B, CHIP or TRIM48 for proteasomal degradation, or deubiquitinated by USP11 for DNA damage repair. P, phosphorylation; Me, methylation; Ub, ubiquitination. ASK1, apoptosis signal-regulating kinase 1; CDK5, cyclin-dependent kinase 5; CHIP, carboxy-terminus of Hsc70 interacting protein; CSNK1a1, casein kinase 1α; DNA-PK, DNA-dependent protein kinase; GRHL3, grainyhead like transcription factor 3; MRE11, meiotic recombination 11; PRMT1, protein arginine methyltransferase 1; Trx, thioredoxin; WDR24, WD-40 repeat-containing protein 24; ULK3, Unc51-likekinase 3; USP11, ubiquitin specific peptidase 11.

Figure 4
Figure 4

Regulation of CARM1 by post-translational modifications. The activity, stability, substrate specificity and the biological consequences of CARM1 are regulated by phosphorylation (P), methylation (Me), ubiquitination (Ub) and O-GlcNAcylation (GlcNAc). The amino acid residues modified by PTMs are also shown. K, lysine; R, arginine; S, serine; T, threonine; Y, tyrosine. CARM1, coactivator-associated arginine methyltransferase 1; ERα, estrogen receptor α; GSK-3β, glycogen synthase kinase 3β; PKA, protein kinase A; PKC, protein kinase C; OGT, O-GlcNAc transferase; SKP2, S-phase kinase-associated protein 2.

Figure 5
Figure 5

Regulation of PRMT5 by post-translational modifications. Stress-responsive kinases phosphorylate PRMT5 at various residues to modulate PRMT5 activity, stability and substrate specificity and their biological consequences, particularly in cancer. PRMT5 is also regulated by K48-linked ubiquitination for proteasomal degradation or K63-linked ubiquitination for histone methylation and tumorigenesis. PRMT5 is further methylated by CARM1 to inhibit gene expression via histone H4R3 methylation. P, phosphorylation; Me, methylation; Ub, ubiquitination. The amino acid residues modified by PTMs are also shown. K, lysine; R, arginine; S, serine; T, threonine; Y, tyrosine. CARM1, coactivator-associated arginine methyltransferase 1; CHIP, carboxy-terminus of Hsc70 interacting protein; JAK2V617F, constitutively active Janus kinase 2 mutant; LKB1, liver kinase B1; MP, myosin phosphatase; MEP50, methylosome protein 50; ROK, RhoA activating kinase; RioK1, Rio kinase 1; PDZ, proteins containing PDZ domain; pICln, chloride nucleotide-sensitive channel 1A; PKCι, Protein kinase C iota; PRMT5, protein arginine methyltransferase 5; SGK, serum and glucocorticoid inducible protein kinase; Src, Src kinase; TRAF6, TNF receptor associated factor 6; ULK3, Unc51-likekinase 3; 14-3-3, 14-3-3 protein; 53BP1, p53-binding protein 1.

Figure 6
Figure 6

PRMTs regulate DNA virus infection. (A) PRMTs regulate the nuclear-cytoplasmic shuttling of viral proteins. (B) PRMTs methylate EBV EBNA1 and EBNA2 to regulate viral gene expression, or methylate NCL to promote its binding to G-quadruplexes within EBNA1 mRNA, thereby inhibiting EBNA1 production to prevent immune activation. PRMT1 also methylates KSHV LANA to modulate viral latent reactivation. (C) KSHV ORF59 interacts with and suppresses PRMT5-mediated H4R3 methylation to promote viral reactivation. (D) HPV E6 inhibits PRMTs-mediated p53-responsive gene expression and triggers CARM1 proteasomal degradation. (E) PRMT1 methylates ADV L4-100K to ensure viral late protein synthesis and viral yield. CARM1, coactivator-associated arginine methyltransferase 1; COPR5, cooperator of protein arginine methyltransferase 5; EBV, Epstein-Barr virus; E6P, E6-associated protein; HCMV, human cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus type 1; KSHV, kaposi sarcoma-associated herpesvirus; NCL, nucleolin; SRPK1, serine-arginine protein kinase 1; PRMT, protein arginine methyltransferase; SR, splicing factors; TPL, tripartite leader sequence; Me, methylation; P, phosphorylation; Ub, ubiquitination.

Figure 7
Figure 7

PRMTs regulate RNA virus infection. (A) PRMT1 methylates VP1 to promote IBDV replication. (B) PRMTs methylate G3BP1 and SARS-CoV-2 N protein to inhibit stress granule formation. PRMT1 also methylates N protein to promote viral genome packaging. (C) PRMT5 methylates ACE2 to promote its N-glycosylation and interaction with SARS-CoV-2 S1 protein. (D) PRMT1 inhibits HCV NS3 helicase activity and enhances STAT1-mediated interferon response or FOXO3-mediated anti-liver injury response via methylation. PRMT1 activity is also inhibited by PP2A or alcohol. (E) PRMT6 methylates HIV Vpr to inhibit nuclear export of viral RRE-containing RNA, or methylates NC to inhibit reverse transcription, or methylates Tat to inhibit its proteasomal degradation and Cyclin T1-mediated viral gene expression. PRMT1 methylates Sam68 to promote viral RNA nuclear transport or methylates hnRNP A1 to inhibit IRES-mediated viral protein translation, the latter of which is enhanced by PRMT5 methyaltion of hnRNP A1. PRMT5 or PRMT7 also interact with Vpr to inhibit its proteasomal degradation. (F) PRMT1 and PRMT5 catalyse histone H4R3me2 to inhibit HBV viral transcription. PRMT5 also methylates HBc to promote its dissociation from HBV cccDNA. The viral protein HBx triggers proteasomal degradation of PRMT1 and WDR77 or inhibits the expression of LINC01431, which can interact with and enhance PRMT1 stability by blocking HBx-mediated ubiquitination and degradation. ACE2, Angiotensin‐converting enzyme 2; cccDNA, covalently closed circular DNA; CUL4, cullin 4; DDB1, DNA damage-binding protein 1; FOXO3, forkhead box O3; G3BP1, Ras GTPase-activating protein-binding proteins 1; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IBDV, infectious bursal disease virus; IRES, internal ribosomal entry site; JMJD6, Jumonji C domain-containing protein 6; PIAS1, protein inhibitor of activated STAT 1; PP2A, protein phosphatase 2A; PRMT, protein arginine methyltransferase; ROC1, regulator of cullins 1; RRE, rev response element; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT1, signal transducer and activator of transcription 1; WDR77, WD-40 repeat-containing protein77; ZHX2, zinc fingers and homeoboxes 2; Me, methylation; Ub, ubiquitination.

Figure 8
Figure 8

PRMTs regulate antiviral innate immunity. PRMT1 methylates cGAS to repress the DNA sensor cGAS/STING signaling pathway, while methylating TBK1 to promote its activation and downstream signals. PRMT1 also methylates STAT1 to promote its nuclear DNA binding and IFN response. PRMT2 stimulates the TLR4/IRF3 pathway to enhance IFN-β production and methylates TRAF6 to prevent its ubiquitination and interaction with MAVS. PRMT3 inhibits RIG-1 activation. PRMT5 methylates cGAS and IFI16 to inhibit cGAS/STING, while interacting with nuclear cGAS to promote H3R2me2s and IFN gene expression. PRMT5 also negatively regulates the transcription of NLRC5, which is required for antigen presentation. PRMT6 sequesters IRF3 to inhibit its activation. PRMT7 methylates MAVS to inhibit its interaction with RIG-I, while PRMT9 methylates MAVS to inhibit its aggregation and autoactivation. cGAS, cyclic GMP-AMP synthase; IFI16, interferon gamma inducible protein 16; IFN, interferon; IRF3, interferon regulatory factor 3; ISG, interferon-stimulated gene; JAK, Janus kinase; MAVS, mitochondrial antiviral signaling protein; MDA5, Melanoma differentiation-associated gene 5; MHC-1, major histocompatibility complex, class I; NEMO, inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; NLRC5, NLR family CARD domain containing 5; RIG-1, retinoic acid-inducible gene I; PRMT, protein arginine methyltransferase; STAT1, signal transducer and activator of transcription 1; STING, stimulator of interferon gene; TBK1, TANK binding kinase 1; TLR4, toll like receptor 4; TRAF6, TNF receptor associated factor 6; TRIF, TIR domain containing adaptor molecule 1; Me, methylation; P, phosphorylation; Ub, ubiquitination.

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