Abstract
Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.
Highlights
To combat viral infections, host organisms have developed an intricate defense network comprising the intrinsic, innate, and adaptive immune response
All cytomegaloviruses characterized so far express an abundant immediate-early protein, termed immediate-early 1 (IE1), that binds to the cellular restriction factor promyelocytic leukemia protein (PML) and antagonizes its repressive activity on viral gene expression
Expression of human cytomegalovirus (HCMV) IE1 allows rat cytomegalovirus infection in human cells. This indicates that the cellular restriction factor PML forms an important barrier for cross-species infection of cytomegaloviruses that might be overcome by adaptation of IE1 protein function
Summary
Host organisms have developed an intricate defense network comprising the intrinsic, innate, and adaptive immune response. While innate and adaptive defense mechanisms rely on pathogen-induced activation, the intrinsic immune system is conferred by constitutively expressed restriction factors mediating a front-line defense against invading pathogens [1]. During the evolutionary “arms race”, viruses have evolved means to evade or directly counteract these antiviral host factors, mainly by expressing antagonistic proteins. The evolutionary pressure that restriction factors and antagonists have exerted on each other resulted in further adaptations at the virus-host interface. Restriction factors are often less effective against viral infections of their natural host but constitute potent barriers to cross-species infections [3]
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