Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferroptosis, and other pathways. CIL56-induced cell death requires a catalytically active protein S-acyltransferase complex comprising the enzyme ZDHHC5 and an accessory subunit GOLGA7. The ZDHHC5-GOLGA7 complex is mutually stabilizing and localizes to the plasma membrane. CIL56 inhibits anterograde protein transport from the Golgi apparatus, which may be lethal in the context of ongoing ZDHHC5-GOLGA7 complex-dependent retrograde protein trafficking from the plasma membrane to internal sites. Other oxime-containing small molecules, structurally distinct from CIL56, may trigger cell death through the same pathway. These results define an unconventional form of nonapoptotic cell death regulated by protein S-acylation.

中文翻译：

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ZDHHC5-GOLGA7蛋白酰基转移酶复合物可促进非凋亡性细胞死亡。

致命的小分子是发现和表征新型细胞死亡途径和生化机制的有用探针。在这里，我们报告合成的含肟的小分子胱天蛋白酶独立致死性56（CIL56）诱导非常规形式的非凋亡细胞死亡，不同于尸检，肥大症和其他途径。CIL56诱导的细胞死亡需要包含酶ZDHHC5和辅助亚基GOLGA7的催化活性蛋白S-酰基转移酶复合物。ZDHHC5-GOLGA7复合物相互稳定并位于质膜上。CIL56抑制高尔基体中顺行性蛋白质的运输，这在正在进行的ZDHHC5-GOLGA7依赖复合物的逆行性蛋白质从质膜到内部位点的运输过程中可能是致命的。其他含肟的小分子，在结构上与CIL56不同，可能通过同一途径触发细胞死亡。这些结果定义了一种非常规形式的非凋亡性细胞死亡，受蛋白S-酰化作用调节。