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Review
. 2024 Feb 26:15:1341599.
doi: 10.3389/fmicb.2024.1341599. eCollection 2024.

Role of protein Post-translational modifications in enterovirus infection

Xiaohui Zhao  1 , Yibo Hu  2 , Jun Zhao  1 , Yan Liu  3 , Xueman Ma  4 , Hongru Chen  5 , Yonghua Xing  6
Affiliations
Review

Role of protein Post-translational modifications in enterovirus infection

Xiaohui Zhao et al. Front Microbiol. .

Abstract

Enteroviruses (EVs) are the main cause of a number of neurological diseases. Growing evidence has revealed that successful infection with enteroviruses is highly dependent on the host machinery, therefore, host proteins play a pivotal role in viral infections. Both host and viral proteins can undergo post-translational modification (PTM) which can regulate protein activity, stability, solubility and interactions with other proteins; thereby influencing various biological processes, including cell metabolism, metabolic, signaling pathways, cell death, and cancer development. During viral infection, both host and viral proteins regulate the viral life cycle through various PTMs and different mechanisms, including the regulation of host cell entry, viral protein synthesis, genome replication, and the antiviral immune response. Therefore, protein PTMs play important roles in EV infections. Here, we review the role of various host- and virus-associated PTMs during enterovirus infection.

Keywords: enterovirus infection; enterovirus life cycle; host factors; pathogenesis; post-translation modification.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The enterovirus life cycle depends heavily on diverse host machinery. Step 1. Entry: The three main steps by which EV71 virus particles enter the host cell are adhesion onto the host cell surface, binding of viral particles to cell receptors, and entry of viral particles into cells through endocytic pathways. Step 2. Uncoating and genome release: under the influence of the pH environment of the host cell, the virus sheds its shell and releases its genome. Step 3. Translation and cleavage of viral polyprotein: under the influence of various host proteins, translation of viral RNA is initiated and the resulting polyprotein is cleaved to obtain the structural and non-structural proteins. Step 4. Replication of viral genomes: viral genome replication requires the participation of a large number of host factors and viral proteins to complete the formation of replication organelles (ROs) and genome replication. Step 5. Assembly and release of viral particles: the assembly of viral particles also requires coordination between various viral and host proteins. After the assembly, the virus particles are released into the extracellular space in various ways to initiate the next round of infection.
Figure 2
Figure 2
The antiviral role of ubiquitination in enterovirus infection. (A) TRIM7 recognizes the C-terminal region of 2C via the PRY-SPRY domain, thereby mediating degradation of the 2 BC (Change 2C into 2 BC) protein to inhibit enterovirus replication. (B) TRIM38 disrupts EV71 infection by ubiquitinating cellular proteins that regulate immune signaling pathways or their interactions with viral proteins. (C) TRIM21 mediates the enhancement of type I interferon signaling by interacting with mitochondrial anti-viral signaling protein to catalyze the K27-linked polyubiquitination of mitochondrial anti-viral signaling protein, which inhibits CVB3 infection. (D) TRIM25 mediates RIG-I ubiquitination and restores RIG-I expression and IFN-β production to prevent enterovirus infection. (E) EV71 infection induces ARRDC4 expression Subsequently, ARRDC4 interacts with MDA5 and recruits TRIM65 to increase MDA5 K63 ubiquitination, leading to the activation of the innate signaling pathway; thus, inhibiting EV71 infection.
Figure 3
Figure 3
The proviral role of ubiquitination in enterovirus infection. (A) TRIM21-mediated ubiquitination of SAMHD1 leads to the degradation of SAMHD1, thus promoting EV71 infection. (B) USP4-mediated TRAF6 K48-linked deubiquitination induces the upregulation of RLR-induced NF-κB signaling to suppress the EV71 replication. (C) STUB1 interacts with AGO2 and accelerates the K48-linked ubiquitination of AGO2, thus promoting its degradation and decreasing the RNAi response; thereby promoting EV-71 replication.
Figure 4
Figure 4
The roles of Ub-like modification in enterovirus infection. (A) EV71 3C protein can be SUMO-modified by Ubc9 which decreases the protease activity and protein stability of 3C, thereby decreasing EV71 replication. (B) SUMOylation of the EV71 3D protein cooperates with 3D ubiquitination to increase its stability, eventually promoting the replication of EV71. (C) SUMOylation of REGγ causes it to translocate from the nucleus to the cytoplasm, allowing the possible interaction of REG with viral or host proteins to play a proviral role during CVB3 infection. (D) The VP2 protein of EV71 is modified by NEDD8 at lysine 69, reducing its stability and decreasing viral replication. (E) Protein ISGylation blocks coxsackievirus pathology by increasing antiviral effectors, IFIT1/3 proteins, and metabolic reprogramming.
Figure 5
Figure 5
The roles of acetylation in the infection of enterovirus. (A) SIRT1 can inhibit the acetylation and RNA dependent RNA polymerase activity of 3D pol, thus reducing viral genome replication. SIRT1 also interacts with the 5′ UTR of EV71 RNA to disrupt viral RNA translation. (B) CVB3 infection induces histone deacetylase2 (HDAC2) activity, and treatment with HDAC inhibitors can inhibit CVB3 replication. (C) Inhibition of HDAC activity increases the formation of autophagosomes which promote CVB3 replication and ultimately exacerbate the severity of CVB3-induced myocarditis. (D) CVB3 infection induces the expression of HDAC1 and Bax while suppressing SIRT1 and Bcl-2, in addition to upregulating acetylated p53. (E) NAT8 promotes EV71 replication by increasing the stability of 2B, 3AB, and 3C proteins in an acetyltransferase-activity-dependent manner.
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