title: The Prolyl Isomerase Pin1 Promotes the Herpesvirus-Induced Phosphorylation-Dependent Disassembly of the Nuclear Lamina Required for Nucleocytoplasmic Egress.
abstract: The nuclear lamina lines the inner nuclear membrane providing a structural framework for the nucleus. Cellular processes, such as nuclear envelope breakdown during mitosis or nuclear export of large ribonucleoprotein complexes, are functionally linked to the disassembly of the nuclear lamina. In general, lamina disassembly is mediated by phosphorylation, but the precise molecular mechanism is still not completely understood. Recently, we suggested a novel mechanism for lamina disassembly during the nuclear egress of herpesviral capsids which involves the cellular isomerase Pin1. In this study, we focused on mechanistic details of herpesviral nuclear replication to demonstrate the general importance of Pin1 for lamina disassembly. In particular, Ser22-specific lamin phosphorylation consistently generates a Pin1-binding motif in cells infected with human and animal alpha-, beta-, and gammaherpesviruses. Using nuclear magnetic resonance spectroscopy, we showed that binding of Pin1 to a synthetic lamin peptide induces its cis/trans isomerization in vitro. A detailed bioinformatic evaluation strongly suggests that this structural conversion induces large-scale secondary structural changes in the lamin N-terminus. Thus, we concluded that a Pin1-induced conformational change of lamins may represent the molecular trigger responsible for lamina disassembly. Consistent with this concept, pharmacological inhibition of Pin1 activity blocked lamina disassembly in herpesvirus-infected fibroblasts and consequently impaired virus replication. In addition, a phospho-mimetic Ser22Glu lamin mutant was still able to form a regular lamina structure and overexpression of a Ser22-phosphorylating kinase did not induce lamina disassembly in Pin1 knockout cells. Intriguingly, this was observed in absence of herpesvirus infection proposing a broader importance of Pin1 for lamina constitution. Thus, our results suggest a functional model of similar events leading to disassembly of the nuclear lamina in response to herpesviral or inherent cellular stimuli. In essence, Pin1 represents a regulatory effector of lamina disassembly that promotes the nuclear pore-independent egress of herpesviral capsids.
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Hutterer
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Hanife
authors.initials: H
authors.lastname: Bahsi
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Sonntag
authors.affiliation: Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anselm H C
authors.identifier: 0000-0003-1328-2695
authors.initials: AH
authors.lastname: Horn
authors.affiliation: Institute for Virology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Benedikt B
authors.initials: BB
authors.lastname: Kaufer
authors.affiliation: Division of Clinical Virology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Department of Chemistry, University of Bergen, Bergen, Norway.
authors.forename: Torgils
authors.initials: T
authors.lastname: Fossen
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D015153:Blotting, Western; D002213:Capsid / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006564:Herpesviridae; D006566:Herpesviridae Infections / Q000378:metabolism / Q000821:virology*; D006801:Humans; D034882:Lamins; D009682:Magnetic Resonance Spectroscopy; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism*; D034881:Nuclear Lamina / Q000378:metabolism / Q000821:virology*; D010766:Phosphorylation; D014779:Virus Replication / Q000502:physiology*
chemical_list: D034882:Lamins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase