# Deamidation-mediated metabolic reprogramming by KSHV in cell proliferation and tumorigenesis

> **NIH NIH R00** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $248,882

## Abstract

PROJECT SUMMARY
Human Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiological agent of multiple cancers. However,
the molecular details concerning the tumorigenesis of KSHV are not well understood. Our recent studies indicate
that herpesviruses employ protein deamidation to evade innate immune response. To probe the role of protein
deamidation in fundamental biological processes, we performed a focused screen targeting cellular glutamine
amidotransferases (GAT), a potential protein deamidases family. We identified one glutamine amidotransferase
as a negative regulator of NF-κB activation. In our preliminary studies, we found that the GAT possessed intrinsic
protein deamidating ability to deamidate NF-κB transcription factor to dampen its ability to transactivate NF-κB
genes. Remarkably, deamidation promoted aerobic glycolysis to promote cell proliferation and tumorigenesis.
Furthermore, KSHV hijacks the cellular mechanism to induce NF-κB deamidation and promote cell proliferation,
thereby inducing tumor formation. Our findings support the overarching hypothesis a nucleotide biosynthetic
enzyme deamidates a NF-κB subunit to reprogram metabolism, thus promoting cell proliferation and
tumorigenesis, and that KSHV hijacks this mechanism to achieve persistent infection. To test this central
hypothesis, I propose three aims in this project: 1) Elucidate the GAT-mediated deamidation of a NF-κB subunit
and downregulation of NF-κB activation; 2) Delineate the metabolic reprogramming by GAT-mediated
deamidation; and 3) Characterize a viral mechanism that hijacks the cellular deamidation to promote proliferation
and tumor formation during KSHV latent infection.
In the K99 phase, I will achieve the following three sub aims: 1) characterize the molecular detail of the NF-κB
deamidation (Aim 1A); 2) examine the role of deamidation in innate immune defense (Aim 1B); and 3) dissect
the mechanism of deamidation-mediated metabolic reprogramming (Aim 2A).
In the R00 phase, I will complete Aim 2 by defining the role of NF-κB deamidation in proliferation and
tumorigenesis of diverse cancer cell lines. Furthermore, I will investigate the mechanism by which KSHV
promotes NF-κB deamidation and define its role in metabolism and tumorigenesis during KSHV infection.
In summary, the K99/R00 project will characterize novel functions of a cellular metabolic enzyme (in nucleotide
synthesis) and a key transcription factor (a NF-κB subunit), and elucidate a new mechanism governing metabolic
reprogramming to drive cell proliferation, thereby offering fresh insight into the metabolic regulation during KSHV
infection. It will establish the foundation for my long-term career goals to study protein deamidations in cellular
metabolism, KSHV-associated tumorigenesis and translational applications to antiviral/antitumor therapies.

## Key facts

- **NIH application ID:** 10409889
- **Project number:** 4R00DE028973-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jun Zhao
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,882
- **Award type:** 4N
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409889

## Citation

> US National Institutes of Health, RePORTER application 10409889, Deamidation-mediated metabolic reprogramming by KSHV in cell proliferation and tumorigenesis (4R00DE028973-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409889. Licensed CC0.

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