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

Award Number: F31AI186315
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/03/2025
PERIOD OF PERFORMANCE END DATE: 01/02/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $38,600 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	001	2	4/13/2026	NON-COMPETING CONTINUATION	$576
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	000	2	1/22/2026	NON-COMPETING CONTINUATION	$38,024
														Subtotal = $38,600

Issue Date FY: 2024 ( Subtotal = $37,460 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	001	1	7/5/2024	NEW	$0
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	000	1	7/5/2024	NEW	$37,460
														Subtotal = $37,460

Grand Total All Awards = $76,060

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

Award Number: F31AI186315

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/03/2025

PERIOD OF PERFORMANCE END DATE: 01/02/2028

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