# KSHVmediated regulation of proline metabolism

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $313,840

## Abstract

Project Summary/Abstract
Metabolic reprograming has been readily recognized as part of the hallmarks of cancer. Particularly,
proline metabolism is critically important for tumor metastasis, as pyrroline-5-carboxylate reductase
(P5CR), a key mitochondrial proline biosynthesis enzyme, is highly overexpressed in various
metastasized tumors and to promote tumor cell growth. This suggests that the proline synthesis
pathway is an attractive target for cancer treatment. Kaposi’s sarcoma-associated herpesvirus
(KSHV) is one of oral herpesviruses and causes Kaposi’s sarcoma and pleural effusion lymphoma.
The proposed research is directed toward investigating the molecular mechanism of KSHV-mediated
regulation of proline metabolism. We have shown that KSHV K1 glycoprotein elicits intracellular
signal transduction for growth transformation in a C-terminal immunoreceptor tyrosine-based
activation motif (ITAM)-dependent manner. Surprisingly, we discovered (Aim 1) that the
unphosphorylated K1 directly interacted with mitochondrial P5CR in an ITAM-independent manner
and this interaction activated its enzymatic activity, increasing intracellular proline synthesis.
Furthermore, KSHV gene screening identified that ORF75, an enzyme-deficient viral glutamine
amidotransferase (vGAT), functions as a substrate recruiter by binding one of host GATs, PFAS
(phosphoribosylformylglycinamidine synthetase), and vGAT/PFAS enzyme complex deamidates
intracellular nucleic acid sensors, evading host innate immune response. Furthermore, our
proteome-wide deamidation screen discovered (Aim 2) that the vGAT/PFAS complex effectively
induced the deamidation of P5C synthase (P5CS) during KSHV lytic replication. Based on these, we
hypothesize a novel viral regulation of proline metabolism where KSHV utilizes two gene products
to deregulate proline synthesis pathway: K1 activates the enzymatic activity of P5CR in an ITAM-
independent manner and vGAT collaborates with host PFAS to induce the deamidation of P5CS,
which ultimately synergizes to enhance proline synthesis and cell growth transformation (Aim 3). The
proposed studies will provide an understanding of a novel oncogenic strategy of KSHV to induce
proline metabolism for virus-induced pathogenesis.

## Key facts

- **NIH application ID:** 9846212
- **Project number:** 5R01DE028521-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jae U Jung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,840
- **Award type:** 5
- **Project period:** 2019-01-07 → 2020-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846212

## Citation

> US National Institutes of Health, RePORTER application 9846212, KSHVmediated regulation of proline metabolism (5R01DE028521-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9846212. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*