KSHV proteins containing signal peptides.

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.内质网（Endoplasmic Reticulum, ER）驻留型热休克蛋白70（HSP70）伴侣蛋白BiP（HSPA5）在维持并恢复内质网内蛋白质折叠稳态的过程中发挥关键作用。BiP的功能在癌症与病毒感染的细胞中常出现失调，进而为细胞带来促癌及促病毒增殖的生存优势。我们针对卡波西肉瘤相关疱疹病毒（Kaposi’s sarcoma-associated herpesvirus, KSHV）——一种与免疫功能低下患者所患癌症相关的致瘤性γ疱疹病毒——感染过程中的BiP功能开展了研究。研究结果显示，在KSHV感染的裂解期，受感染的上皮细胞内BiP的蛋白水平会上调。这种上调过程不依赖于未折叠蛋白反应（unfolded protein response, UPR），后者是一条调控BiP可用性的主要信号通路。对BiP进行遗传与药理学抑制，可阻断KSHV的病毒复制，并降低KSHV感染细胞的增殖能力与存活水平。值得注意的是，BiP抑制能够限制其他α、β疱疹病毒以及痘病毒的传播，且对正常细胞的毒性极低。本研究表明，BiP是开发针对双链DNA病毒的广谱抗病毒疗法的潜在靶点，同时也是干预KSHV相关恶性肿瘤的极具前景的治疗候选靶点。