title: Simian virus 40 induces lamin A/C fluctuations and nuclear envelope deformation during cell entry.
abstract: The canonical gate of viruses and viral genomes into the nucleus in non-dividing cells is the nuclear pore, embedded within the nuclear envelope. However, we found that for SV40, the nuclear envelope poses a major hurdle to infection: FISH analysis revealed that the majority of viral DNA remains trapped in the ER; silencing of Lamin A/C rendered the cells more susceptible to infection; and proliferating cells are more susceptible to infection than quiescent cells. Surprisingly, we observed that following SV40 infection the nuclear envelope, including lamins A/C, B1, B2 and the nuclear pore complex, was dramatically deformed, as seen by immunohistochemistry. The infection induced fluctuations in the level of lamin A/C, dephosphorylation of an unknown epitope and leakage to the cytoplasm just prior to and during nuclear entry. Deformations were transient, and the spherical structure of the nuclear envelope was restored subsequent to nuclear entry. Nuclear envelope deformations and lamin A/C dephosphorylation depended on caspase-6 cleavage of lamin A/C. Notably, we have previously reported that inhibition of caspase-6 abolishes SV40 infection. Taken together the results suggest that alterations of the nuclear lamina, induced by the infecting virus, are involved in the nuclear entry of the SV40 genome. We propose that SV40 utilize this unique, previously unknown mechanism for direct trafficking of its genome from the ER to the nucleus. As SV40 serves as a paradigm for the pathogenic human BK, JC and Merkel cell polyomavirus, this study suggests nuclear entry as a novel drug target for these infections.
authors.affiliation: Department of Hematology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Veronika
authors.initials: V
authors.lastname: Butin-Israeli
authors.forename: Orly
authors.initials: O
authors.lastname: Ben-nun-Shaul
authors.forename: Idit
authors.initials: I
authors.lastname: Kopatz
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Adam
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimi
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
authors.forename: Ariella
authors.initials: A
authors.lastname: Oppenheim
mesh_terms: D000818:Animals; D053178:Caspase 6 / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D016679:Genome, Viral / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D009685:Nuclear Envelope / Q000502:physiology*; D022022:Nuclear Pore / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D034904:Lamin Type A; D034921:Lamin Type B; C440308:lamin C; D053178:Caspase 6