The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we follow heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

中文翻译：

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内切糖苷酶HPSE破坏先天防御反应可促进细胞存活

抵御环境压力和抵御入侵的动力是各种生活中普遍存在的特征。尽管已详细描述了许多典型的信号传导级联，但仍不清楚这些途径如何相互作用以产生对各种刺激的协调反应。为了剖析这些联系，我们遵循乙酰肝素酶（HPSE），该蛋白以在细胞外基质中具有糖苷内切活性而闻名，但最近被认为可通过未知机制驱动各种形式的晚期疾病。使用单纯疱疹病毒1（HSV-1）感染作为模型细胞扰动，我们证明HPSE的作用超出其已建立的酶促作用，以限制多种形式的细胞内在防御，并通过入侵的病原体促进宿主细胞重编程。我们揭示了不含HPSE的细胞天生具有抗感染能力，并通过多种放大的防御机制来抵消病毒的接管。通过对转录调节和细胞死亡的基本过程的独特掌握，HPSE代表了一种具有广泛治疗潜力的有效细胞交集。