BiP/GRP78 is a pro-viral factor for diverse dsDNA viruses that promotes the survival and proliferation of cells upon KSHV infection.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012660
Guillermo Najarro, Kevin Brackett, Hunter Woosley, Leah C Dorman, Vincent Turon-Lagot, Sudip Khadka, Catya Faeldonea, Osvaldo Kevin Moreno, Adriana Ramirez Negron, Christina Love, Ryan Ward, Charles Langelier, Frank McCarthy, Carlos Gonzalez, Joshua E Elias, Brooke M Gardner, Carolina Arias
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引用次数: 0

Abstract

The Endoplasmic Reticulum (ER)-resident HSP70 chaperone BiP (HSPA5) plays a crucial role in maintaining and restoring protein folding homeostasis in the ER. BiP's function is often dysregulated in cancer and virus-infected cells, conferring pro-oncogenic and pro-viral advantages. We explored BiP's functions during infection by the Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus associated with cancers of immunocompromised patients. Our findings reveal that BiP protein levels are upregulated in infected epithelial cells during the lytic phase of KSHV infection. This upregulation occurs independently of the unfolded protein response (UPR), a major signaling pathway that regulates BiP availability. Genetic and pharmacological inhibition of BiP halts KSHV viral replication and reduces the proliferation and survival of KSHV-infected cells. Notably, inhibition of BiP limits the spread of other alpha- and beta-herpesviruses and poxviruses with minimal toxicity for normal cells. Our work suggests that BiP is a potential target for developing broad-spectrum antiviral therapies against double-stranded DNA viruses and a promising candidate for therapeutic intervention in KSHV-related malignancies.

BiP/GRP78是多种dsDNA病毒的促病毒因子,在KSHV感染后可促进细胞的存活和增殖。
内质网(ER)驻留的 HSP70 伴侣 BiP(HSPA5)在维持和恢复ER中的蛋白质折叠平衡方面发挥着至关重要的作用。在癌症和病毒感染细胞中,BiP 的功能经常失调,从而带来促癌和促病毒优势。卡波西肉瘤相关疱疹病毒(KSHV)是一种与免疫功能低下患者癌症相关的致癌γ-疱疹病毒,我们探讨了BiP在卡波西肉瘤相关疱疹病毒(KSHV)感染过程中的功能。我们的研究结果表明,在 KSHV 感染的溶解阶段,受感染的上皮细胞中 BiP 蛋白水平上调。这种上调与未折叠蛋白反应(UPR)无关,UPR 是调节 BiP 可用性的主要信号通路。遗传和药物抑制 BiP 可阻止 KSHV 病毒复制,减少 KSHV 感染细胞的增殖和存活。值得注意的是,抑制 BiP 可限制其他α-和β-疱疹病毒和痘病毒的传播,而对正常细胞的毒性却很小。我们的研究表明,BiP 是开发针对双链 DNA 病毒的广谱抗病毒疗法的潜在靶点,也是对 KSHV 相关恶性肿瘤进行治疗干预的有希望的候选靶点。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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