Lipoxin A4 (LXA4) is an endogenous lipid mediator with compelling anti-inflammatory and proresolution properties. Studies done to assess the role of arachidonic acid pathways of the host in Kaposi's sarcoma-associated herpesvirus (KSHV) biology helped discover that KSHV infection hijacks the proinflammatory cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) pathways and concurrently reduces anti-inflammatory LXA4 secretion to maintain KSHV latency in infected cells. Treatment of KSHV-infected cells with LXA4 minimizes the activation of inflammatory and proliferative signaling pathways, including the NF-κB, AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, but the exact mechanism of action of LXA4 remains unexplored. Here, using mass spectrometry analysis, we identified components from the minichromosome maintenance (MCM) protein and chromatin-remodeling complex SMARCB1 and SMARCC2 to be LXA4-interacting host proteins in KSHV-infected cells. We identified a higher level of nuclear aryl hydrocarbon receptor (AhR) in LXA4-treated KSHV-infected cells than in untreated KSHV-infected cells, which probably facilitates the affinity interaction of the nucleosome complex protein with LXA4. We demonstrate that SMARCB1 regulates both replication and transcription activator (RTA) activity and host hedgehog (hh) signaling in LXA4-treated KSHV-infected cells. Host hedgehog signaling was modulated in an AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-S6 kinase-dependent manner in LXA4-treated KSHV-infected cells. Since anti-inflammatory drugs are beneficial as adjuvants to conventional and immune-based therapies, we evaluated the potential of LXA4 treatment in regulating programmed death-ligand 1 (PD-L1) on KSHV-carrying tumor cells. Overall, our study identified LXA4-interacting host factors in KSHV-infected cells, which could help provide an understanding of the mode of action of LXA4 and its therapeutic potential against KSHV.IMPORTANCE The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV's pathogenesis.

中文翻译：

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通过染色质调节和宿主刺猬信号同时控制卡波西氏肉瘤相关疱疹病毒的生命周期：Lipoxin A4的治疗潜力的新前景。

Lipoxin A4（LXA4）是一种内源性脂质介体，具有令人信服的抗炎和高分辨率特性。评估宿主的花生四烯酸途径在卡波西氏肉瘤相关疱疹病毒（KSHV）生物学中的作用的研究有助于发现KSHV感染劫持了促炎性环氧合酶2（COX-2）和5-脂氧合酶（5-LO）途径，以及同时减少抗炎LXA4分泌，以维持感染细胞中的KSHV潜伏期。用LXA4处理被KSHV感染的细胞可最大程度地减少炎症和增殖信号通路的激活，包括NF-κB，AKT和细胞外信号调节激酶1/2（ERK1 / 2）通路，但LXA4的确切作用机制仍未开发。在这里，使用质谱分析，我们从微染色体维持（MCM）蛋白和染色质重塑复合物SMARCB1和SMARCC2中鉴定出了在KSHV感染的细胞中与LXA4相互作用的宿主蛋白。我们发现与未处理的KSHV感染的细胞相比，LXA4处理的KSHV感染的细胞中较高水平的核芳基烃受体（AhR），这可能促进了核小体复合蛋白与LXA4的亲和力相互作用。我们证明SMARCB1调节LXA4处理的KSHV感染细胞中的复制和转录激活因子（RTA）活性和宿主刺猬（hh）信号。在LXA4处理的KSHV感染的细胞中，以AMP激活的蛋白激酶（AMPK）-雷帕霉素（mTOR）-S6激酶依赖性的哺乳动物靶标调节宿主刺猬的信号。由于抗炎药可作为常规疗法和基于免疫疗法的佐剂，因此我们评估了LXA4治疗在调节携带KSHV的肿瘤细胞上编程的死亡配体1（PD-L1）的潜力。总体而言，我们的研究在感染KSHV的细胞中鉴定出了与LXA4相互作用的宿主因子，这可以帮助您了解LXA4的作用方式及其对KSHV的治疗潜力。由主要复制和转录激活因子KSHV蛋白（称为RTA）调控的关键事件。病毒基因组的染色质修饰决定了宿主中病毒生命周期的阶段。在这里，我们报告LXA4与宿主染色质调节剂，特别是SMARCB1相互作用，后者上调KSHV ORF50启动子。还已经认识到SMARCB1是一种肿瘤抑制蛋白，它控制着许多与刺猬（hh）信号通路相关的致瘤事件。我们还观察到LXA4处理可降低PD-L1表达，并且PD-L1表达是KSHV在宿主中生存和维持的重要免疫逃避策略。我们的研究强调了LXA4在KSHV生物学中的作用，并强调KSHV在下调宿主中LXA4分泌以建立潜伏期方面具有战略意义。这项研究还发现了LXA4及其可靶向受体AhR在KSHV发病机理中的治疗潜力。我们还观察到LXA4处理可降低PD-L1表达，并且PD-L1表达是KSHV在宿主中生存和维持的重要免疫逃避策略。我们的研究强调了LXA4在KSHV生物学中的作用，并强调KSHV在下调宿主中LXA4分泌以建立潜伏期方面具有战略意义。这项研究还发现了LXA4及其可靶向受体AhR在KSHV发病机理中的治疗潜力。我们还观察到LXA4处理可降低PD-L1表达，并且PD-L1表达是KSHV在宿主中生存和维持的重要免疫逃避策略。我们的研究强调了LXA4在KSHV生物学中的作用，并强调KSHV在下调宿主中LXA4分泌以建立潜伏期方面具有战略意义。这项研究还发现了LXA4及其可靶向受体AhR在KSHV发病机理中的治疗潜力。