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Ancestral zinc-finger bearing protein MucR in alpha-proteobacteria: A novel xenogeneic silencer?

ABSTRACT: The MucR/Ros family protein is conserved in alpha-proteobacteria and characterized by its zinc-finger motif that has been proposed as the ancestral domain from which the eukaryotic C2H2 zinc-finger structure evolved. In the past decades, accumulated evidences have revealed MucR as a pleiotropic transcriptional regulator that integrating multiple functions such as virulence, symbiosis, cell cycle and various physiological processes. Scattered reports indicate that MucR mainly acts as a repressor, through oligomerization and binding to multiple sites of AT-rich target promoters. The N-terminal region and zinc-finger bearing C-terminal region of MucR mediate oligomerization and DNA-binding, respectively. These features are convergent to those of xenogeneic silencers such as H-NS, MvaT, Lsr2 and Rok, which are mainly found in other lineages. Phylogenetic analysis of MucR homologs suggests an ancestral origin of MucR in alpha- and delta-proteobacteria. Multiple independent duplication and lateral gene transfer events contribute to the diversity and phyletic distribution of MucR. Finally, we posed questions which remain unexplored regarding the putative roles of MucR as a xenogeneic silencer and a general manager in balancing adaptation and regulatory integration in the pangenome context.

SUBMITTER: Jiao J

PROVIDER: S-EPMC7710501 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ancestral zinc-finger bearing protein MucR in alpha-proteobacteria: A novel xenogeneic silencer?

Jiao Jian J Tian Chang-Fu CF

Computational and structural biotechnology journal 20201119

The MucR/Ros family protein is conserved in alpha-proteobacteria and characterized by its zinc-finger motif that has been proposed as the ancestral domain from which the eukaryotic C2H2 zinc-finger structure evolved. In the past decades, accumulated evidences have revealed MucR as a pleiotropic transcriptional regulator that integrating multiple functions such as virulence, symbiosis, cell cycle and various physiological processes. Scattered reports indicate that MucR mainly acts as a repressor, ...[more]

PMID: 33304460

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Project description:Given the unprecedented scale of the recent Ebola and Zika viral epidemics, it is crucial to understand the biology of host factors with broad antiviral action in order to develop novel therapeutic approaches. Here, we look into one such factor: zinc finger antiviral protein (ZAP) inhibits a variety of RNA and DNA viruses. Alternative splicing results in two isoforms that differ at their C termini: ZAPL (long) encodes a poly(ADP-ribose) polymerase (PARP)-like domain that is missing in ZAPS (short). Previously, it has been shown that ZAPL is more antiviral than ZAPS, while the latter is more induced by interferon (IFN). In this study, we discovered and confirmed the expression of two additional splice variants of human ZAP: ZAPXL (extralong) and ZAPM (medium). We also found two haplotypes of human ZAP. Since ZAPL and ZAPS have differential activities, we hypothesize that all four ZAP isoforms have evolved to mediate distinct antiviral and/or cellular functions. By taking a gene-knockout-and-reconstitution approach, we have characterized the antiviral, translational inhibition, and IFN activation activities of individual ZAP isoforms. Our work demonstrates that ZAPL and ZAPXL are more active against alphaviruses and hepatitis B virus (HBV) than ZAPS and ZAPM and elucidates the effects of splice variants on the action of a broad-spectrum antiviral factor.IMPORTANCE ZAP is an IFN-induced host factor that can inhibit a wide range of viruses, and there is great interest in fully characterizing its antiviral mechanism. This is the first study that defines the antiviral capacities of individual ZAP isoforms in the absence of endogenous ZAP expression and, hence, cross talk with other isoforms. Our data demonstrate that ZAP is expressed as four different forms: ZAPS, ZAPM, ZAPL, and ZAPXL. The longer ZAP isoforms better inhibit alphaviruses and HBV, while all isoforms equally inhibit Ebola virus transcription and replication. In addition, there is no difference in the abilities of ZAP isoforms to enhance the induction of type I IFN expression. Our results show that the full spectrum of ZAP activities can change depending on the virus target and the relative levels of basal expression and induction by IFN or infection.

Dataset Information

Ancestral zinc-finger bearing protein MucR in alpha-proteobacteria: A novel xenogeneic silencer?

Publications

Ancestral zinc-finger bearing protein MucR in alpha-proteobacteria: A novel xenogeneic silencer?

Similar Datasets

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