Molecular Basis for Nuclear Egress of Herpesviruses

• Applicant: Professor Dr. Thomas C. Mettenleiter
• Subject Area: Virology
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226088690

• Final Report Year: 2020

Final Report Abstract

Nuclear egress of herpesvirus nucleocapsids is a novel vesicle-mediated transport pathway of large cargo, like herpesvirus nucleocapsids, through the nuclear envelope from nucleoplasm to cytosol. In a previous project we showed that the nuclear egress complex consisting of a dimer of viral pUL31 and pUL34 proteins is necessary for nuclear egress and sufficient for vesicle formation from the inner nuclear membrane. In this project we analyzed the functional aspects of NEC formation which was greatly assisted by the elucidation, in cooperation with another group, of the crystal structure of the NEC and derived oligo- and polymeric structures. The involvement of cellular proteins in this process was tested and we showed that cellular proteins including Torsins A/B and the LINC complex play a role in nuclear egress. Moreover, we identified and characterized nuclear envelope breakdown as an in vitro mechanism to overcome a defect in NEC-mediated, regulated nuclear egress.

Publications

• 2013. Glycoproteins gB and gH are required for syncytium formation but not for herpesvirus-induced nuclear envelope breakdown. J. Virol. 87, 9733-41
  Schulz KS, Klupp BG, Granzow H, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.01401-13)
• 2013. Mapping of sequences in pseudorabies virus pUL34 that are required for formation and function of the nuclear egress complex. J. Virol. 87, 4475-4485
  Paßvogel L, Trübe P, Schuster F, Klupp BG, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.00021-13)
• 2014. Identification of conserved amino acids in pUL34 which are critical for function of the pseudorabies virus nuclear egress complex. J. Virol. 88, 6224-6231
  Paßvogel L, Janke U, Klupp BG, Granzow H, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.00595-14)
• 2014. Pseudorabies virus pUL46 induces activation of ERK1/2 and regulates herpesvirus-induced nuclear envelope breakdown. J. Virol. 88, 6003-6011
  Schulz KS, Liu X, Klupp BG, Granzow H, Cohen JI, Mettenleiter, TC
  (See online at https://doi.org/10.1128/JVI.00501-14)
• 2015. A single herpesvirus protein can mediate vesicle formation in the nuclear envelope. J. Biol. Chem. 290, 6962-6974
  Lorenz M, Vollmer B, Unsay JD, Klupp BG, García-Sáez AJ, Mettenleiter TC, Antonin W
  (See online at https://doi.org/10.1074/jbc.M114.627521)
• 2015. Crystal Structure of the Herpesvirus Nuclear Egress Complex Provides Insights into Inner Nuclear Membrane Remodeling. Cell Rep. 13, 2645- 2652
  Zeev-Ben-Mordehai T, Weberruß M, Lorenz M, Cheleski J, Hellberg T, Whittle C, El Omari K, Vasishtan D, Dent KC, Harlos K, Franzke K, Hagen C, Klupp BG, Antonin W, Mettenleiter TC, Grünewald K
  (See online at https://doi.org/10.1016/j.celrep.2015.11.008)
• 2015. Functional characterization of nuclear trafficking signals in pseudorabies virus pUL31. J. Virol. 89, 2002-2012
  Paßvogel L, Klupp BG, Granzow H, Fuchs W, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.03143-14)
• 2015. Herpesvirus nuclear egress: pseudorabies virus can simultaneously induce nuclear envelope breakdown and exit the nucleus via the envelopment-deenvelopment-pathway. Virus Res. 209, 76-86
  Schulz KS, Klupp BG, Granzow H, Paßvogel L, Mettenleiter TC
  (See online at https://doi.org/10.1016/j.virusres.2015.02.001)
• 2015. Structural Basis of Vesicle Formation at the Inner Nuclear Membrane. Cell 163, 1692-1701.
  Hagen C, Dent KC, Zeev-Ben-Mordehai T, Grange M, Bosse JB, Whittle C, Klupp BG, Siebert CA, Vasishtan D, Bäuerlein FJ, Cheleski J, Werner S, Guttmann P, Rehbein S, Henzler K, Demmerle J, Adler B, Koszinowski U, Schermelleh L, Schneider G, Enquist LW, Plitzko JM, Mettenleiter TC, Grünewald K
  (See online at https://doi.org/10.1016/j.cell.2015.11.029)
• 2016. Breaching the Barrier-The Nuclear Envelope in Virus Infection. J. Mol. Biol. 428, 1949-61
  Mettenleiter TC
  (See online at https://doi.org/10.1016/j.jmb.2015.10.001)
• 2016. Nuclear Egress of Herpesviruses. Adv. Virus Res. 94, 81-140
  Hellberg T, Paßvogel L, Schulz KS, Klupp BG, Mettenleiter TC
  (See online at https://doi.org/10.1016/bs.aivir.2015.10.002)
• 2017. Integrity of the linker of nucleoskeleton and cytoskeleton is required for efficient herpesvirus nuclear egress. J. Virol. 91, e00330-17
  Klupp BG, Hellberg T, Granzow H, Franzke K, Dominguez Gonzalez B, Goodchild RE, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.00330-17)
• 2017. Lysine 242 within Helix 10 of the pseudorabies virus nuclear egress complex pUL31 component is critical for primary envelopment of nucleocapsids. J. Virol. 91, e01182-17
  Rönfeldt S, Klupp BG, Franzke K, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.01182-17)
• 2020. Function of torsin AAA+ ATPases in pseudorabies virus nuclear egress. Cells 9, 738; doi:10.3390/cells 9030738
  Hölper JE, Klupp BG, Luxton GWG, Franzke K, Mettenleiter TC
  (See online at https://doi.org/10.3390/cells9030738)
• 2020. Generation and characterization of monoclonal antibodies specific for the Pseudorabies Virus nuclear egress complex. Virus Res. 2020 Jul 17;287: 198096
  Hölper JE, Reiche S, Franzke K, Mettenleiter TC, Klupp BG
  (See online at https://doi.org/10.1016/j.virusres.2020.198096)
• 2020. Mutational functional of the pseudorabies virus nuclear egress complex – nucleocapsid interaction. J. Virol. 94, e01910-19
  Rönfeldt S, Franzke K, Hölper J, Klupp BG, Mettenleiter TC
  (See online at https://doi.org/10.1128/JVI.01910-19)