African swine fever, caused by the African swine fever virus (ASFV), is a viral hemorrhagic disease that affects domestic pigs and wild boars. ASFV infection causes extensive tissue damage, and the associated mechanism is poorly understood. Pyroptosis is characterized by the activation of inflammatory caspases and pore formation in the cellular plasma membrane, resulting in the release of inflammatory cytokines and cell damage. How ASFV infection regulates pyroptosis remains unclear. Here, using siRNA assay and overexpression methods, we report that ASFV infection regulated pyroptosis by cleaving the pyroptosis execution protein gasdermin A (GSDMA). ASFV infection activated caspase-3 and caspase-4, which specifically cleaved GSDMA at D75-P76 and D241-V242 to produce GSDMA into five fragments, including GSDMA-N, GSDMA-N, and GSDMA-N fragments at the N-terminal end of GSDMA. Only GSDMA-N, which was produced in the late stage of ASFV infection, triggered pyroptosis and inhibited ASFV replication. The fragments, GSDMA-N and GSDMA-N, lose the ability to induce pyroptosis. Overall ASFV infection differentially regulates pyroptosis by GSDMA in the indicated phase, which may be conducive to its own replication. Our findings reveal a novel molecular mechanism for the regulation of pyroptosis.

中文翻译：

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非洲猪瘟病毒感染通过活性 caspase-3 和 caspase-4 裂解 Gasdermin A 来调节细胞焦亡


非洲猪瘟由非洲猪瘟病毒（ASFV）引起，是一种影响家猪和野猪的病毒性出血性疾病。 ASFV 感染会导致广泛的组织损伤，但相关机制尚不清楚。细胞焦亡的特征是炎症性半胱天冬酶的激活和细胞质膜中孔的形成，导致炎症细胞因子的释放和细胞损伤。 ASFV 感染如何调节细胞焦亡尚不清楚。在这里，我们使用 siRNA 测定和过表达方法，报告 ASFV 感染通过裂解焦亡执行蛋白 Gasdermin A (GSDMA) 来调节焦亡。 ASFV感染激活caspase-3和caspase-4，特异性地在D75-P76和D241-V242处切割GSDMA，将GSDMA产生5个片段，包括GSDMA-N、GSDMA-N和N端的GSDMA-N片段GSMA 的。只有ASFV感染后期产生的GSDMA-N引发细胞焦亡并抑制ASFV复制。 GSDMA-N 和 GSDMA-N 片段失去诱导细胞焦亡的能力。总体而言，ASFV 感染在指定阶段通过 GSDMA 差异性调节细胞焦亡，这可能有利于其自身复制。我们的研究结果揭示了调节细胞焦亡的新分子机制。