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.

项目摘要人类Kaposi与肉瘤相关的疱疹病毒（KSHV）是多种癌症的病因。然而，关于KSHV肿瘤发生的分子细节尚不清楚。我们最近的研究表明疱疹病毒员工蛋白质死亡逃避了先天免疫反应。探测蛋白质的作用在基本生物学过程中，我们进行了靶向细胞谷氨酰胺的聚焦筛查潜在的蛋白质脱胺酶家族酰胺转移酶（GAT）。我们确定了一个谷氨酰胺酰胺转移酶作为NF-κB激活的负调节剂。在我们的初步研究中，我们发现GAT具有固有的破坏NF-κB转录因子以抑制其反式激活NF-κB的能力基因。值得注意的是，死亡促进了有氧糖酵解以促进细胞增殖和肿瘤发生。此外，KSHV劫持了诱导NF-κB死亡并促进细胞增殖的细胞机制从而诱导肿瘤形成。我们的发现支持核苷酸生物合成的总体假设酶死亡使NF-κB亚基为重编代谢，从而促进细胞增殖和肿瘤发生，KSHV劫持了这种机制以实现持续感染。测试这个中央假设，我在该项目中提出了三个目标：1）阐明GAT介导的NF-κB亚基的死亡 NF-κB激活的下调； 2）通过GAT介导的描述代谢重编程脱氨3）表征一种病毒机制，该机制劫持了细胞脱氨基以促进增殖 KSHV潜在感染期间的肿瘤形成。在K99阶段，我将达到以下三个亚目标：1）表征NF-κB的分子细节脱氨基（AIM 1A）； 2）检查脱氨酸在先天免疫防御中的作用（AIM 1B）； 3）解剖死亡介导的代谢重编程的机制（AIM 2A）。在R00阶段，我将通过定义NF-κB死亡在增殖和潜水癌细胞系的肿瘤发生。此外，我将研究KSHV的机制促进NF-κB死亡，并定义其在KSHV感染期间的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的新功能（在核苷酸中合成）和关键转录因子（NF-κB亚基），并阐明了一种管理代谢的新机制重新编程以驱动细胞增殖，从而在KSHV期间对代谢调节提供新的见解感染。它将为我的长期职业目标建立基础，以研究细胞中的蛋白质死亡蛋白代谢，KSHV相关的肿瘤发生以及对抗病毒/抗肿瘤疗法的转化应用。