Nonstructural NSs protein of rift valley fever virus interacts with pericentromeric DNA sequences of the host cell, inducing chromosome cohesion and segregation defects.
Rift Valley fever virus (RVFV) is an emerging, highly pathogenic virus; RVFV infection can lead to encephalitis, retinitis, or fatal hepatitis associated with hemorrhagic fever in humans, as well as death, abortions, and fetal deformities in animals. RVFV nonstructural NSs protein, a major factor of the virulence, forms filamentous structures in the nuclei of infected cells. In order to further understand RVFV pathology, we investigated, by chromatin immunoprecipitation, immunofluorescence, fluorescence in situ hybridization, and confocal microscopy, the capacity of NSs to interact with the host genome. Our results demonstrate that even though cellular DNA is predominantly excluded from NSs filaments, NSs interacts with some specific DNA regions of the host genome such as clusters of pericentromeric gamma-satellite sequence. Targeting of these sequences by NSs was correlated with the induction of chromosome cohesion and segregation defects in RVFV-infected murine, as well as sheep cells. Using recombinant nonpathogenic virus rZHDeltaNSs210-230, expressing a NSs protein deleted of its region of interaction with cellular factor SAP30, we showed that the NSs-SAP30 interaction was essential for NSs to target pericentromeric sequences, as well as for induction of chromosome segregation defects. The effect of RVFV upon the inheritance of genetic information is discussed with respect to the pathology associated with fetal deformities and abortions, highlighting the main role played by cellular cofactor SAP30 on the establishment of NSs interactions with host DNA sequences and RVFV pathogenesis.
Mansuroglu
Z
Z
Régulation de la Transcription et Maladies Génétiques, CNRS UPR2228, Université Paris Descartes, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
Josse
T
T
Gilleron
J
J
Billecocq
A
A
Leger
P
P
Bouloy
M
M
Bonnefoy
E
E
D000818:Animals; D002460:Cell Line; D002503:Centromere / Q000235:genetics*; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D020090:Chromosome Segregation / Q000502:physiology; D004276:DNA, Satellite / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006655:Histone Deacetylases / Q000378:metabolism; D054884:Host-Pathogen Interactions; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018613:Microscopy, Confocal; D012296:Rift Valley fever virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D012756:Sheep; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
D004276:DNA, Satellite; C491870:Sap30 protein, mouse; D017361:Viral Nonstructural Proteins; D006655:Histone Deacetylases