Research area: Molecular Virology
The order Nidovirales (families Coronaviridae, Mesoniviridae, Arteriviridae and Roniviridae) comprises viruses with extremely large RNA genomes and includes important animal and human pathogens, such as SARS and MERS coronavirus. The nidovirus replication/transcription complex (RTC) consists of an exceptionally large number of viral enzymes. This also includes a 3'-5' exoribonuclease (ExoN) presumed to be involved in proofreading mechanisms during viral replication. In the first funding period, the Ziebuhr group characterized the biochemical properties of this enzyme for representative viruses of the subfamilies Corona- and Torovirinae and has extended these studies to other nonstructural proteins (nsp7, 8, 9, 10, 12, 13) that are thought to form the coronavirus/nidovirus "core replicase". Furthermore, essential cis-active RNA elements conserved across the genus Alphacoronavirus were identified and a detailed characterization of the replication/transcription complex of the newly discovered Mesoniviridae was initiated. In this context, the Ziebuhr group characterized the mesonivirus main protease and characterized the proteolytic processing of the mesonivirus "core" replicase. Together, these studies provide the basis for comparative studies of common and distinct mechanisms involved in the replication of nidoviruses with large- (30 kb) and medium-size (20 kb) RNA genomes using biochemical and reverse-genetics approaches.
Project-related publications of the investigator:
- Kanitz M, Blanck S, Heine A, Gulyaeva AA, Gorbalenya AE, Ziebuhr J*, Diederich WE*. Structural basis for catalysis and substrate specificity of a 3C-like cysteine protease from a mosquito mesonivirus. Virology 2019; 533:21-33. *corresponding authors
- Tvarogová J, Madhugiri R, Bylapudi G, Ferguson LJ, Karl N, Ziebuhr J. Identification and characterization of a human coronavirus 229E nonstructural protein 8-associated RNA 3'-terminal adenylyltransferase activity. J Virol 2019; 93:e00291-19.
- Durzynska I, Sauerwald M, Karl N, Madhugiri R, Ziebuhr J. Characterization of a bafinivirus exoribonuclease activity. J Gen Virol 2018; 99:1253-1260.
- Madhugiri R, Karl N, Petersen D, Lamkiewicz K, Fricke M, Wend U, Scheuer R, Marz M, Ziebuhr J. Structural and functional conservation of cis-acting RNA elements in coronavirus 5'-terminal genome regions. Virology 2018; 517:44-55.
- Müller C, Hardt M, Schwudke D, Neuman BW, Pleschka S, Ziebuhr J. Inhibition of Cytosolic phospholipase A2alpha impairs an early step of coronavirus replication in cell culture. J Virol 2018; 92:01463-17.
- Kindler E, Gil-Cruz C, Spanier J, Li Y, Wilhelm J, Rabouw HH, Zust R, Hwang M, V'Kovski P, Stalder H, Marti S, Habjan M, Cervantes-Barragan L, Elliot R, Karl N, Gaughan C, van Kuppeveld FJ, Silverman RH, Keller M, Ludewig B, Bergmann CC, Ziebuhr J, Weiss SR, Kalinke U, Thiel V. Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication. PLoS Pathog 2017; 13:e1006195.
- Poppe M, Wittig S, Jurida L, Bartkuhn M, Wilhelm J, Müller H, Beuerlein K, Karl N, Bhuju S, Ziebuhr J, Schmitz ML, Kracht M. The NF-kappaB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. PLoS Pathog 2017; 13:e1006286.
- Snijder EJ, Decroly E, Ziebuhr J. The nonstructural proteins directing coronavirus RNA synthesis and processing. Adv Virus Res 2016; 96:59-126.
- Madhugiri R, Fricke M, Marz M, Ziebuhr J. Coronavirus cis-acting RNA elements. Adv Virus Res 2016; 96:127-163.
- Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J. Discovery of an RNA virus 3'-5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci USA 2006; 103:5108-5113.