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ADP-ribosylation systems in bacteria and viruses.

ABSTRACT: ADP-ribosylation is an ancient posttranslational modification present in all kingdoms of life. The system likely originated in bacteria where it functions in inter- and intra-species conflict, stress response and pathogenicity. It was repeatedly adopted via lateral transfer by eukaryotes, including humans, where it has a pivotal role in epigenetics, DNA-damage repair, apoptosis, and other crucial pathways including the immune response to pathogenic bacteria and viruses. In other words, the same ammunition used by pathogens is adapted by eukaryotes to fight back. While we know quite a lot about the eukaryotic system, expanding rather patchy knowledge on bacterial and viral ADP-ribosylation would give us not only a better understanding of the system as a whole but a fighting advantage in this constant arms race. By writing this review we hope to put into focus the available information and give a perspective on how this system works and can be exploited in the search for therapeutic targets in the future. The relevance of the subject is especially highlighted by the current situation of being amid the world pandemic caused by a virus harbouring and dependent on a representative of such a system.

SUBMITTER: Mikolcevic P

PROVIDER: S-EPMC8120803 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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ADP-ribosylation systems in bacteria and viruses.

Mikolčević Petra P Hloušek-Kasun Andrea A Ahel Ivan I Mikoč Andreja A

Computational and structural biotechnology journal 20210417

ADP-ribosylation is an ancient posttranslational modification present in all kingdoms of life. The system likely originated in bacteria where it functions in inter- and intra-species conflict, stress response and pathogenicity. It was repeatedly adopted via lateral transfer by eukaryotes, including humans, where it has a pivotal role in epigenetics, DNA-damage repair, apoptosis, and other crucial pathways including the immune response to pathogenic bacteria and viruses. In other words, the same ...[more]

PMID: 34025930

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Project description:UNLABELLED:ADP-ribosylation is a posttranslational protein modification in which ADP-ribose is transferred from NAD(+) to specific acceptors to regulate a wide variety of cellular processes. The macro domain is an ancient and highly evolutionarily conserved protein domain widely distributed throughout all kingdoms of life, including viruses. The human TARG1/C6orf130, MacroD1, and MacroD2 proteins can reverse ADP-ribosylation by acting on ADP-ribosylated substrates through the hydrolytic activity of their macro domains. Here, we report that the macro domain from hepatitis E virus (HEV) serves as an ADP-ribose-protein hydrolase for mono-ADP-ribose (MAR) and poly(ADP-ribose) (PAR) chain removal (de-MARylation and de-PARylation, respectively) from mono- and poly(ADP)-ribosylated proteins, respectively. The presence of the HEV helicase in cis dramatically increases the binding of the macro domain to poly(ADP-ribose) and stimulates the de-PARylation activity. Abrogation of the latter dramatically decreases replication of an HEV subgenomic replicon. The de-MARylation activity is present in all three pathogenic positive-sense, single-stranded RNA [(+)ssRNA] virus families which carry a macro domain: Coronaviridae (severe acute respiratory syndrome coronavirus and human coronavirus 229E), Togaviridae (Venezuelan equine encephalitis virus), and Hepeviridae (HEV), indicating that it might be a significant tropism and/or pathogenic determinant. IMPORTANCE:Protein ADP-ribosylation is a covalent posttranslational modification regulating cellular protein activities in a dynamic fashion to modulate and coordinate a variety of cellular processes. Three viral families, Coronaviridae, Togaviridae, and Hepeviridae, possess macro domains embedded in their polyproteins. Here, we show that viral macro domains reverse cellular ADP-ribosylation, potentially cutting the signal of a viral infection in the cell. Various poly(ADP-ribose) polymerases which are notorious guardians of cellular integrity are demodified by macro domains from members of these virus families. In the case of hepatitis E virus, the adjacent viral helicase domain dramatically increases the binding of the macro domain to PAR and simulates the demodification activity.

Dataset Information

ADP-ribosylation systems in bacteria and viruses.

Publications

ADP-ribosylation systems in bacteria and viruses.

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