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.
Highlights
The nuclear envelope represents a physical barrier separating the nucleus from the cytoplasm
The recently discovered alternative mechanism for the nuclear export of large messenger ribonucleoprotein complexes is noteworthy. This process is mechanistically similar to the nuclear egress of herpesviruses, which appear to utilize cellular pathways and effectors to release assembled capsids from the host nucleus
While vesicle formation and scission events at nuclear membranes are increasingly understood in greater detail, the precise mechanism of the preceding disassembly of the nuclear lamina still awaits a defined molecular characterization
Summary
The nuclear envelope represents a physical barrier separating the nucleus from the cytoplasm. It consists of three distinct elements: nuclear membranes, nuclear pores, and the proteinaceous network of the nuclear lamina. The main constituents of the nuclear lamina are nuclear lamins that belong to type V intermediate filament proteins and are grouped into type A and B. Lamins are composed of a central alpha-helical coiled-coil rod domain flanked by globular head (N-terminal) and tail (C-terminal) domains. Parallel lamin dimers are formed by coiled-coil interactions of the rod domains of two lamin monomers. The lamin dimers form polar head-to-tail polymers, and several polymers associate side by side into lamin filaments [2]
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