# The One Ring to Rule Them All: How ICP0’s Ring Finger in Alliance with the Host Protein CIN85 Regulates Protein Trafficking and Communication

> **NIH NIH F31** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $37,460

## Abstract

Abstract
 Following productive, lytic infection in mucosal epithelial cells located at the portal of entry in the body, herpes
simplex virus-1 (HSV-1) establishes a lifelong, silent infection in sensory neurons. The virus is occasionally
reactivated due to weakened immune response or stress causing diseases that range in severity from benign
cold sores to encephalitis. HSV-1 contributes to exacerbation of neurodegenerative diseases such as
Alzheimer's and facilitates infection by other pathogens such as HIV-1.
 To infect and persist in the host, HSV-1 has evolved strategies to counteract host antiviral responses. The
immediate early protein of the virus Infected Cells Protein No 0 (ICP0) plays a fundamental role in this process.
ICP0 is classified as a non-essential protein for the virus in cell cultures, particularly at a high multiplicity of
infection, however it is well-documented that ICP0 is important to promote successful onset of lytic infection
and productive reactivation of viral genomes from latency. Following its expression, ICP0 localizes in the
nucleus where it activates viral gene transcription by degrading cellular repressors to viral DNA and innate
immunity factors. This activity is facilitated by the ICP0 E3 ubiquitin ligase function mapped to the residues
116-156 which contains a Zn2+-binding Really Interesting New Gene (RING) finger domain. The onset of virus
replication triggers translocation of ICP0 to the cytoplasm where its functions have been scantily explored.
Cytoplasmic ICP0 interacts with the adaptor protein CIN85, a binding partner of the Cbl E3 ligase, which has
a major role in cell surface receptor internalization, endocytic processing and protein sorting. Known
consequences of this interaction include the internalization of the viral entry receptor Nectin-1 from the surface
of infected cells to facilitate virus spread. We recently discovered that the ICP0/CIN85 interaction and the ICP0
RF domain were critical for exocytosis of numerous hostile factors, including innate immunity components and
autophagy related factors within extracellular vesicles (EVs) released by infected cells. Based on these
observations, we hypothesize that as ICP0 enters the cytoplasm following virus replication, it associates
with CIN85-positive vesicular structures and determines endosome and EV proteome content via its
ICP0 E3 ubiquitin ligase activity. This appears to be a novel mechanism by which the virus suppresses
host protein functions. We have designed two aims to test this hypothesis. In Aim 1, we will determine the role
of ICP0 in protein trafficking. In Aim 2, we will determine the impact of ICP0/CIN85 interaction for HSV-1
infection. These studies will address the importance of interaction of ICP0 with the endocytosis adaptor
CIN85 and will delineate this novel mechanism by which ICP0 regulates host protein functions via
subjugation of the endocytosis and exocytosis pathways.

## Key facts

- **NIH application ID:** 10995894
- **Project number:** 1F31AI186315-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Sarah Lasnier
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,460
- **Award type:** 1
- **Project period:** 2025-01-03 → 2028-01-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995894

## Citation

> US National Institutes of Health, RePORTER application 10995894, The One Ring to Rule Them All: How ICP0’s Ring Finger in Alliance with the Host Protein CIN85 Regulates Protein Trafficking and Communication (1F31AI186315-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995894. Licensed CC0.

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