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

KSHV 在细胞增殖和肿瘤发生中脱酰胺介导的代谢重编程

基本信息

批准号：
10426391
负责人：
Jun Zhao
金额：
$ 24.89万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426391
关键词：
Acquired Immunodeficiency Syndrome Anatomy Aspartate Biological Biological Markers Biological Process Biology Cancer Patient Cancer cell line Carbamyl Phosphate Cell Proliferation Cells Cellular Metabolic Process Data Dihydroorotase Disease Down-Regulation Enzymes Etiology Family Foundations Genes Glutamine Glycolysis Goals Grant Herpesviridae Herpesviridae Infections Human Human Herpesvirus 8 Immune Innate Immune Response Kaposi Sarcoma Lesion Ligase Link Location Malignant Neoplasms Mediating Metabolic Metabolism Modality Modification Molecular Multicentric Angiofollicular Lymphoid Hyperplasia Nucleic Acids Nucleotide Biosynthesis Nucleotides Oncogenic Oral cavity Oral mucous membrane structure Palate Kaposi&apos s Sarcoma Patients Phase Post-Translational Protein Processing Prognosis Proteins Pyrimidine Regulation Research Role Sampling Signal Transduction Simplexvirus Skin Testing Time Ursidae Family Viral Viral Load result Virus Latency Work aerobic glycolysis base cancer therapy career cellular targeting chronic infection deamidation gammaherpesvirus immune activation insight latent infection novel nucleotide metabolism pathogen patient stratification prevent primary effusion lymphoma protein function targeted cancer therapy transcarbamylase transcription factor translational applications tumor tumorigenesis

项目摘要

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.

项目概要人类卡波西肉瘤相关疱疹病毒 (KSHV) 是多种癌症的病原体。我们最近的研究表明，有关 KSHV 肿瘤发生的分子细节尚不清楚。疱疹病毒利用蛋白质脱酰胺来逃避先天免疫反应，以探讨蛋白质的作用。在基本生物过程中的脱酰胺作用中，我们针对细胞谷氨酰胺进行了聚焦筛选酰胺转移酶（GAT），一个潜在的蛋白质脱酰胺酶家族我们鉴定了一种谷氨酰胺酰胺转移酶。在我们的初步研究中，我们发现 GAT 具有内在的 NF-κB 激活负调节作用。蛋白质脱酰胺能力使 NF-κB 转录因子脱酰胺，从而抑制其反式激活 NF-κB 的能力值得注意的是，脱酰胺促进了有氧糖酵解，从而促进细胞增殖和肿瘤发生。此外，KSHV 劫持细胞机制诱导 NF-κB 脱酰胺并促进细胞增殖，我们的研究结果支持了核苷酸生物合成的总体假设。酶使 NF-κB 亚基脱酰胺以重新编程代谢，从而促进细胞增殖和肿瘤发生，并且 KSHV 劫持此机制以实现持续感染以测试此中枢。假设，我提出这个项目的三个目标：1) 阐明 GAT 介导的 NF-κB 亚基脱酰胺作用以及 NF-κB 激活的下调；2) 描述 GAT 介导的代谢重编程脱酰胺作用；3) 表征劫持细胞脱酰胺作用以促进增殖的病毒机制 KSHV潜伏感染期间的肿瘤形成。在K99阶段，我将实现以下三个子目标：1）表征NF-κB的分子细节脱酰胺（目标 1A）；2）检查脱酰胺在先天免疫防御中的作用（目标 1B）；以及 3）分析脱酰胺介导的代谢重编程机制（目标 2A）。在 R00 阶段，我将通过定义 NF-κB 脱酰胺在增殖和增殖中的作用来完成目标 2 此外，我将研究 KSHV 的机制。促进 NF-κB 脱酰胺并确定其在 KSHV 感染期间代谢和肿瘤发生中的作用。总之，K99/R00 项目将表征细胞代谢酶（在核苷酸中）的新功能。合成）和关键转录因子（NF-κB 亚基），并阐明了控制代谢的新机制重新编程以驱动细胞增殖，从而为 KSHV 期间的代谢调节提供新的见解它将为我研究细胞中蛋白质脱酰胺的长期职业目标奠定基础。代谢、KSHV 相关肿瘤发生以及抗病毒/抗肿瘤治疗的转化应用。