Singh Rajnish Kumar, Bose Dipayan, Robertson Erle S
Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
J Virol. 2021 May 24;95(12). doi: 10.1128/JVI.02063-20.
The hypoxic microenvironment and metabolic reprogramming are two major contributors to the phenotype of oncogenic virus-infected cells. Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes hypoxia-inducible factor 1α (HIF1α) and reprograms cellular metabolism. We investigated the comparative transcriptional regulation of all major genes involved in fatty acid and amino acid metabolism in KSHV-positive and -negative cells grown under normoxic or hypoxic conditions. We show a distinct regulation of genes involved in both fatty acid and amino acid metabolism in KSHV-positive cells grown in either normoxic or hypoxic conditions, with a particular focus on genes involved in the acetyl coenzyme A (acetyl-CoA) pathway. The fatty acid binding protein (FABP) family of genes, specifically FABP1, FABP4, and FABP7, was also observed to be synergistically upregulated in hypoxia by KSHV. This pattern of FABP gene expression was also seen in naturally infected KSHV BC3 or BCBL1 cells when compared to KSHV-negative DG75 or BL41 cells. Two KSHV-encoded antigens, which positively regulate HIF1α, the viral G-protein coupled receptor (vGPCR), and the latency-associated nuclear antigen (LANA) were shown to drive upregulation of the FABP gene transcripts. Suppression of FABPs by RNA interference resulted in an adverse effect on hypoxia-dependent viral reactivation. Overall, this study provides new evidence, which supports a rationale for the inhibition of FABPs in KSHV-positive cells as potential strategies, for the development of therapeutic approaches targeting KSHV-associated malignancies. Hypoxia is a detrimental stress to eukaryotes and inhibits several cellular processes, such as DNA replication, transcription, translation, and metabolism. Interestingly, the genome of Kaposi's sarcoma-associated herpesvirus (KSHV) is known to undergo productive replication in hypoxia. We investigated the comparative transcriptional regulation of all major genes involved in fatty acid and amino acid metabolism in KSHV-positive and -negative cells grown under normoxic or hypoxic conditions. Several metabolic pathways were observed differentially regulated by KSHV in hypoxia, specifically, the fatty acid binding protein (FABP) family genes (FABP1, FABP4, and FABP7). KSHV-encoded antigens, vGPCR and LANA, were shown to drive upregulation of the FABP transcripts. Suppression of FABPs by RNA interference resulted in an adverse effect on hypoxia-dependent viral reactivation. Overall, this study provides new evidence, which supports a rationale for the inhibition of FABPs in KSHV-positive cells as potential strategies, for the development of therapeutic approaches targeting KSHV-associated malignancies.
缺氧微环境和代谢重编程是致癌病毒感染细胞表型的两个主要促成因素。卡波西肉瘤相关疱疹病毒（KSHV）感染可稳定缺氧诱导因子1α（HIF1α）并使细胞代谢重编程。我们研究了在常氧或缺氧条件下培养的KSHV阳性和阴性细胞中，参与脂肪酸和氨基酸代谢的所有主要基因的比较转录调控。我们发现，在常氧或缺氧条件下培养的KSHV阳性细胞中，参与脂肪酸和氨基酸代谢的基因有明显的调控，特别关注参与乙酰辅酶A（acetyl-CoA）途径的基因。还观察到脂肪酸结合蛋白（FABP）基因家族，特别是FABP1、FABP4和FABP7，在缺氧条件下被KSHV协同上调。与KSHV阴性的DG75或BL41细胞相比，在自然感染KSHV的BC3或BCBL1细胞中也观察到这种FABP基因表达模式。两种正向调节HIF1α的KSHV编码抗原，即病毒G蛋白偶联受体（vGPCR）和潜伏相关核抗原（LANA），被证明可驱动FABP基因转录本的上调。通过RNA干扰抑制FABP会对缺氧依赖性病毒再激活产生不利影响。总体而言，本研究提供了新的证据，支持将抑制KSHV阳性细胞中的FABP作为潜在策略的基本原理，以开发针对KSHV相关恶性肿瘤的治疗方法。缺氧是对真核生物有害的应激，会抑制多种细胞过程，如DNA复制、转录、翻译和代谢。有趣的是，已知卡波西肉瘤相关疱疹病毒（KSHV）的基因组在缺氧条件下进行 productive 复制。我们研究了在常氧或缺氧条件下培养的KSHV阳性和阴性细胞中，参与脂肪酸和氨基酸代谢的所有主要基因的比较转录调控。观察到几种代谢途径在缺氧条件下受到KSHV的差异调节，特别是脂肪酸结合蛋白（FABP）家族基因（FABP1、FABP4和FABP7）。KSHV编码的抗原vGPCR和LANA被证明可驱动FABP转录本的上调。通过RNA干扰抑制FABP会对缺氧依赖性病毒再激活产生不利影响。总体而言，本研究提供了新的证据，支持将抑制KSHV阳性细胞中的FABP作为潜在策略的基本原理，以开发针对KSHV相关恶性肿瘤的治疗方法。
