.png){kind=icon}
.png){kind=icon}
Return
Structural insights into the nuclear import of ovine gammaherpesvirus 2 ORF73 LANA homologue
.png){kind=icon}
PRE
AI
N
S
S
P
R
M
R
A
T
D
A
F
DOI：10.1099/jgv.0.002250.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Ovine gammaherpesviruses 2 (OvGHV2), a member of the Macavirus genus within the Orthoherpesviridae family, causes lymphoproliferative diseases in susceptible species, most notably sheep- associated malignant catarrhal fever. Research on OvGHV2 has been hindered by the absence of a permissive cell culture system, limiting investigations into viral replication, entry mechanisms and cell tropism. This challenge constrains progress towards understanding OvGHV2 pathogenesis and developing effective vaccines or therapeutics. We investigated the molecular mechanisms underlying OvGHV2 infection, focusing on the nuclear trafficking pathways of the latency- associated nuclear antigen (LANA), encoded by ORF73. In other gammaherpesviruses, LANA is known to mediate viral episome maintenance, chromatin tethering and latency through its nuclear localization. We identified and functionally characterized a novel bipartite nuclear localization signal (NLS) within the C- terminal region of OvGHV2 LANA and elucidated its interactions with host nuclear import receptors. Using high- resolution crystallography and quantitative binding assays, we mapped the key residues responsible for binding to importin alpha (IMP alpha) and demonstrated isoform- specific variations in binding affinity. Confocal microscopy revealed that the OvGHV2 LANA predominantly localizes to the nucleus through an IMP alpha/beta 1- dependent pathway, as mutation or inhibition of the NLS significantly reduced nuclear accumulation. Interestingly, partial nuclear localization under these conditions suggests an additional IMP alpha/beta 1-independent nuclear import mechanism. Collectively, our biochemical and structural analyses confirm that the identified NLS is essential for IMP alpha- mediated nuclear import of OvGHV2 LANA. These findings provide new insights into OvGHV2 host interactions and establish a molecular basis for developing targeted antiviral strategies against ovine gammaherpesvirus 2 infection.
Keywords:
crystallography
importins
nuclear trafficking
ovine gammaherpesvirus 2
Journal
IF:
4.3
Papers:
9.0K
Citations:
1.6W
Organization
Cited Papers