Piotr Gerlach, PhD
Laboratory of Structural Virology
Translation is one of the major sites of the virus-host battlefront. On one hand, infected cell shuts down most of the translation, activating at the same time innate immune and integrated stress response pathways. At the same time, RNA viruses, being unconditionally dependent on cellular protein synthesis machinery, use a range of strategies to reorganize and exploit cellular translation, forcing ribosomes to translate viral mRNA. We are particularly interested in bunyaviruses – a large and understudied group of segmented, negative-strand RNA viruses. Three of them – Lassa, Rift Valley, and Crimean-Congo viruses, causing high fatality rate haemorrhagic fevers, are listed by WHO among eight pathogens that may cause future pandemics. Given the lack of vaccines and specific antivirals against bunyaviruses, there is a need to explore their molecular repertoire in order to fully understand their infection mechanisms and thus to raise our preparedness against this threat.
Upon infecting the cell, bunyaviruses release into the cytoplasm their viral ribonucleoproteins (vRNPs). Each vRNP contains an RNA genomic segment coated with nucleoproteins (N proteins) and attached to a single, multifunctional, RNA-dependent RNA polymerase (L protein). Bunyaviral vRNPs initiate the transcription of the viral genomic segments into mRNAs by cap-snatching the cytoplasmic host 5′-capped mRNA and by subsequent coupling of the viral transcription with the ongoing translation. Our goal is to unravel molecular details of this unique viral translation strategy. We hypothesize that bunyaviral RNA polymerase hijacks entire translation initiation complex during the cap-snatching step. This in consequence would lead to formation of a direct contact between the transcribing viral polymerase and the leading ribosome, unprecedented in the eukaryotic system. Moreover, we are exploring how the structural elements within the bunyaviral mRNA 5′ and 3′ UTRs mediate translation.
We use a modified mini-replicon system, mimicking bunyaviral transcription and replication inside the cell, in order to identify host factors involved in the bunyaviral transcription and translation, and to monitor changes in the cellular translation landscape. In parallel, we use cryo-EM to visualize viral-host complexes formed at different steps of the bunyaviral mRNA lifetime. We believe that output of our research will open new avenues in the RNA virus field and set the basis for the design of innovative therapies and broad-spectrum antivirals.
Gerlach P, Garland P, Lingaraju M, Salerno-Kochan M, Bonneau F, Basquin J, Jensen TH & Conti E. Structure and regulation of the Nuclear Exosome Targeting Complex guides RNA substrates to the exosome. Mol Cell (2022) 82: 2505-2518, doi.org/10.1016/j.molcel.2022.04.011
Arragain B, Effantin G, Gerlach P, Reguera J, Schoehn G, Cusack S & Malet H. Pre-initiation and elongation structures of full-length La Crosse virus polymerase reveal functionally important conformational changes. Nat Commun (2020) 11: 3590, doi.org/10.1038/s41467-020-17349-4
Lingaraju M, Schuller JM, Falk S, Gerlach P, Bonneau F, Basquin J, Benda C & Conti E (2020) To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome. Cold Spring Harb Symp Quant Biol (2019) 84: 155-163, doi.org/10.1101/sqb.2019.84.040295
Gerlach P, Schuller JM, Bonneau F, Basquin J, Reichelt P, Falk S & Conti E. Distinct and evolutionary conserved structural features of the human nuclear exosome complex. eLife (2018) 7: e38686, doi.org/10.7554/eLife.38686.001
Reguera J, Gerlach P, Rosenthal M, Gaudon S, Coscia F, Günther S & Cusack S. Comparative structural and functional analysis of bunyavirus and arenavirus cap-snatching endonucleases. PLoS Pathog (2016) 12: e1005636, doi.org/10.1371/journal.ppat.1005636
Reguera J, Gerlach P & Cusack S. Towards a structural understanding of RNA synthesis by negative strand RNA viral polymerases. Curr Opin Struct Biol (2016) 36: 75-84, doi.org/10.1016/j.sbi.2016.01.002
Gerlach P, Malet H, Cusack S & Reguera J. Structural insights into bunyavirus replication and its regulation by the vRNA promoter. Cell (2015) 161: 1267–1279, doi.org/10.1016/j.cell.2015.05.006
ABOUT GROUP LEADER
Dr. Piotr Gerlach joined IMol in summer 2021 within the frame of the FNP-founded ReMedy IRAP. Originally from Warsaw, during his PhD in Dr. Stephen Cusack’s group at EMBL in Grenoble, he succeeded in determining the first atomic structure of a bunyaviral polymerase. Securing an EMBO Long Term Fellowship, he joined Prof. Elena Conti’s lab at Max Planck Institute of Biochemistry in Munich, where he used cryo-EM to study multi-subunit complexes involved in RNA metabolism. At IMol, supported by EMBO IG and NCN SONATA BIS grants, Dr. Gerlach’s Laboratory of Structural Virology is studying how infectious RNA viruses reorganize and exploit cellular translation.
National Science Centre, SONATA BIS 12: Bunyaviral strategies to reorganize and exploit cellular translation, (2022/46/E/NZ1/00273), (15.03.2023-14.03.2028), leader: Piotr Gerlach
EMBO Installation Grant: Mechanism of the bunyaviral transcription-translation coupling, (IG 4742), (01.01.2021-31.12.2025), leader: Piotr Gerlach