[F31] Mechanisms of Nuclear Egress in Gamma-herpesviruses
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-03-31
Importo max: 46.302 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an enveloped, double-stranded-DNA g-herpesvirus and
class I carcinogen. KSHV is the causative agent of Kaposi’s sarcoma, primary effusion lymphomas, and
multicentric Castleman’s disease. In sub-Saharan Africa, it has seroprevalence rates as high as 80% and causes
endemic disease. The effectiveness of this oncogenic virus is largely attributed to its ability to reactivate at
opportune times.
During lytic infection, KSHV – like all herpesviruses – translocates newly assembled capsids from the nucleus
into the cytoplasm for maturation into infectious virions. To accomplish this, KSHV utilizes an unusual process
termed “nuclear egress,” in which viral capsids exit the nucleus by undergoing nuclear membrane budding and
fusion events. The nuclear egress complex (NEC) is a conserved, virally encoded heterodimer that is required
for nuclear egress and can bud membranes independently. Prior work from distantly related neurotropic a-
herpesviruses demonstrated that the NEC promotes budding by oligomerizing into hexagonal, membrane-bound
coats. However, recent studies suggested that the oncogenic g-herpesviruses KSHV and EBV may have
structurally and functionally distinct NECs. Therefore, I hypothesize the KSHV NEC has a distinct membrane
remodeling mechanism to support nuclear egress.
The objective of this proposal is to characterize the mechanisms by which KSHV NEC remodels nuclear
membranes to mediate nuclear egress. In Aim 1, I will characterize KSHV NEC function in vivo and visualize
nuclear egress and nuclear membrane remodeling events in KSHV infected cells using TEM and cryo-electron
tomography. In Aim 2, I will use x-ray crystallography, cryo-EM/ET, and structure-guided mutagenesis to
determine the geometry of KSHV NEC coats and the role their formation plays in membrane budding and nuclear
egress. This proposal is innovative as it will use cutting-edge approaches to yield new mechanistic insights into
the process of nuclear egress in g-herpesviruses. It is significant as it will identify key functional regions within
the KSHV NEC to inform the development of anti-KSHV therapeutics designed to block nuclear egress.
This proposal has the potential to make major contributions for the development of therapeutics against
KSHV and its associated cancers. My sponsor, Dr. Ekaterina Heldwein, will ensure that I acquire the technical
and conceptual skills necessary for the successful completion of this project and for my development into a
premier scientist so that I may achieve my long-term career goal of running my own virology lab.
Istituzione: TUFTS UNIVERSITY BOSTON
PI: Ariana Carolina Calderon-Zavala
Progetto: 1F31AI191719-01A1
Settori: National Institute of Allergy and Infectious Diseases
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