Life-Death Trade-offs: HSV-1 ICP27 as a Cellular Context-Dependent Regulator of Intrinsic Apoptosis

ABSTRACT: Herpes simplex virus type 1 (HSV-1) infection represents an established model for studying virus-host interactions, given its ability to modulate cell fate and achieve long-term persistence. Among the immediate early genes, the multifunctional regulatory protein ICP27, encoded by the UL54 gene, plays a pivotal role in coordinating viral gene expression and remodeling host signaling pathways. This study investigates the role of ICP27 in modulating the intrinsic apoptotic pathway in two cell models representative of different stages of infection: hTert RPE-1 epithelial cells, modeling the lytic replication, and SH-SY5Y neuroblastoma cells, mimicking a neuron-like microenvironment. To evaluate the specific function of HSV-1 ICP27 in this field, cells infected with wild-type HSV-1 (HSV-1 w.t.) were compared with a viral vector lacking ICP27 (HSV-1ΔICP27). Analyses were conducted using RT-qPCR for gene quantification, western blotting for protein evaluation, enzymatic assays to measure caspase activity, flow cytometry to determine reactive oxygen species (ROS) production and mitochondrial functionality, and quantitative proteomic approaches for the global characterization of infection-induced protein changes. ICP27 exerts cell type-dependent effects on apoptosis. In epithelial cells, ICP27 promotes programmed cell death by activating caspase-9 and effector caspases (3/7), increasing reactive oxygen species (ROS) generation, altering mitochondrial function, and elevating the Bax/Bcl-2 ratio, indicative of mitochondrial pathway activation. Conversely, in neuron-like cells, ICP27 suppresses apoptotic signaling by reducing caspase activity, limiting oxidative stress, and preserving mitochondrial integrity. These findings position ICP27 as a cellular context-dependent regulator of apoptosis, driving lytic apoptosis in epithelial cells while favoring host cell survival in neuronal environments. This dual behavior underscores HSV-1 adaptability across microenvironments, with implications for viral pathogenesis and therapeutic targeting.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Neuroblast Proliferation

DISEASE(S): Herpes Simplex

SUBMITTER: Davide Barboni  

LAB HEAD: Martina Catani

PROVIDER: PXD071831 | Pride | 2026-06-16

REPOSITORIES: Pride