The universal suppressor mutation restores membrane budding defects in the HSV-1 nuclear egress complex by stabilizing the oligomeric lattice

Draganova, Elizabeth B.; Wang, Hui; Wu, Melanie; Liao, Shiqing; Vu, Amber; Gonzalez-Del Pino, Gonzalo L.; Zhou, Z. Hong; Roller, Richard J.; Heldwein, Ekaterina E.

doi:10.1371/journal.ppat.1011936

The universal suppressor mutation restores membrane budding defects in the HSV-1 nuclear egress complex by stabilizing the oligomeric lattice

Journal Article · Tue Jan 16 00:00:00 EST 2024 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1011936· OSTI ID:2470221

Draganova, Elizabeth B. ^[1]; Wang, Hui ^[2]; Wu, Melanie ^[3]; Liao, Shiqing ^[2]; Vu, Amber ^[4]; Gonzalez-Del Pino, Gonzalo L. ^[5]; Zhou, Z. Hong ^[2]; Roller, Richard J. ^[4]; ^[5]

Tufts University School of Medicine, Boston, MA (United States); Emory University School of Medicine, Atlanta, GA (United States)
University of California, Los Angeles, CA (United States)
The University of Queensland, Brisbane (Australia)
University of Iowa, Iowa City, IA (United States)
Tufts University School of Medicine, Boston, MA (United States)

Nuclear egress is an essential process in herpesvirus replication whereby nascent capsids translocate from the nucleus to the cytoplasm. This initial step of nuclear egress–budding at the inner nuclear membrane–is coordinated by the nuclear egress complex (NEC). Composed of the viral proteins UL31 and UL34, NEC deforms the membrane around the capsid as the latter buds into the perinuclear space. NEC oligomerization into a hexagonal membrane-bound lattice is essential for budding because NEC mutants designed to perturb lattice interfaces reduce its budding ability. Previously, we identified an NEC suppressor mutation capable of restoring budding to a mutant with a weakened hexagonal lattice. Using an established in-vitro budding assay and HSV-1 infected cell experiments, we show that the suppressor mutation can restore budding to a broad range of budding-deficient NEC mutants thereby acting as a universal suppressor. Cryogenic electron tomography of the suppressor NEC mutant lattice revealed a hexagonal lattice reminiscent of wild-type NEC lattice instead of an alternative lattice. Further investigation using x-ray crystallography showed that the suppressor mutation promoted the formation of new contacts between the NEC hexamers that, ostensibly, stabilized the hexagonal lattice. This stabilization strategy is powerful enough to override the otherwise deleterious effects of mutations that destabilize the NEC lattice by different mechanisms, resulting in a functional NEC hexagonal lattice and restoration of membrane budding.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Howard Hughes Medical Institute; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470221

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 1 Vol. 20; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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The universal suppressor mutation restores membrane budding defects in the HSV-1 nuclear egress complex by stabilizing the oligomeric lattice

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