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Human Cytomegalovirus Immediate Early Protein 2 Protein Causes Cognitive Disorder by Damaging Synaptic Plasticity in Human Cytomegalovirus-UL122-Tg Mice

ABSTRACT: Human cytomegalovirus (HCMV) infection is very common in the human population all around the world. Although the majority of HCMV infections are asymptomatic, they can cause neurologic deficits. Previous studies have shown that immediate early protein 2 (IE2, also known as UL122) of HCMV is related with the cognitive disorder mechanism. Due to species isolation, a HCMV-infected animal model could not be established which meant a study into the long-term effects of IE2 on neural development could not be carried out. By establishing HCMV-UL122-Tg mice (UL122 mice), we explored the cognitive behavior and complexity of neuron changes in this transgenic UL122 mice that could consistently express IE2 protein at different ages (confirmed in both 6- and 12-month-old UL122 mice). In the Morris water maze, cognitive impairment was more pronounced in 12-month-old UL122 mice than in 6-month-old ones. At the same time, a decrease of the density of dendritic spines and branches in the hippocampal neurons of 12-month-old mice was observed. Moreover, long-term potentiation was showed to be impaired in 12-month-old UL122 mice. The expressions of several synaptic plasticity-regulated molecules were reduced in 12-month-old UL122 mice, including scaffold proteins postsynaptic density protein 95 (PSD95) and microtubule-associated protein 2 (MAP2). Binding the expression of IE2 was increased in 12-month-old mice compared with 6-month-old mice, and results of statistical analysis suggested that the cognitive damage was not caused by natural animal aging, which might exclude the effect of natural aging on cognitive impairment. All these results suggested that IE2 acted as a pathogenic regulator in damaging synaptic plasticity by downregulating the expression of plasticity-related proteins (PRPs), and this damage increased with aging.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8591137 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Promyelocytic leukemia (PML) bodies are nuclear organelles implicated in intrinsic and innate antiviral defense. The eponymous PML proteins, central to the self-organization of PML bodies, and other restriction factors found in these organelles are common targets of viral antagonism. The 72-kDa immediate-early protein 1 (IE1) is the principal antagonist of PML bodies encoded by the human cytomegalovirus (hCMV). IE1 is believed to disrupt PML bodies by inhibiting PML SUMOylation, while PML was proposed to act as an E3 ligase for IE1 SUMOylation. PML targeting by IE1 is considered to be crucial for hCMV replication at low multiplicities of infection, in part via counteracting antiviral gene induction linked to the cellular interferon (IFN) response. However, current concepts of IE1-PML interaction are largely derived from mutant IE1 proteins known or predicted to be metabolically unstable and globally misfolded. We performed systematic clustered charge-to-alanine scanning mutagenesis and identified a stable IE1 mutant protein (IE1cc172-176) with wild-type characteristics except for neither interacting with PML proteins nor inhibiting PML SUMOylation. Consequently, IE1cc172-176 does not associate with PML bodies and is selectively impaired for disrupting these organelles. Surprisingly, functional analysis of IE1cc172-176 revealed that the protein is hypermodified by mixed SUMO chains and that IE1 SUMOylation depends on nucleosome rather than PML binding. Furthermore, a mutant hCMV expressing IE1cc172-176 was only slightly attenuated compared to an IE1-null virus even at low multiplicities of infection. Finally, hCMV-induced expression of cytokine and IFN-stimulated genes turned out to be reduced rather than increased in the presence of IE1cc172-176 relative to wild-type IE1. Our findings challenge present views on the relationship of IE1 with PML and the role of PML in hCMV replication. This study also provides initial evidence for the idea that disruption of PML bodies upon viral infection is linked to activation rather than inhibition of innate immunity.

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Human Cytomegalovirus Immediate Early Protein 2 Protein Causes Cognitive Disorder by Damaging Synaptic Plasticity in Human Cytomegalovirus-UL122-Tg Mice

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