CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as <i>Legionella pneumophila</i> but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as <i>Burkholderia cenocepacia</i>. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to <i>B. cenocepacia</i> infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of <i>B. cenocepacia</i> with LC3 and acidic compartments accompanied by increased bacterial replication <i>in vitro</i> and <i>in vivo</i>. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to <i>B. cenocepacia</i> infection.

半胱天冬酶-4（CASP4）/半胱天冬酶-11（caspase-11）依赖性炎症小体激活，对于清除侵入宿主胞质的各类革兰氏阴性菌至关重要。此外，CASP4可调控肌动蛋白细胞骨架，以促进携带胞内病原菌（如嗜肺军团菌Legionella pneumophila）的吞噬体成熟，却无法作用于包裹非致病性细菌的吞噬体。尽管如此，学界对于CASP4在液泡内细菌转运过程中的这一非炎症功能仍知之甚少。巨自噬/自噬（macroautophagy/autophagy）是真核细胞内的分解代谢过程，同样参与清除诸如洋葱伯克霍尔德菌Burkholderia cenocepacia在内的胞内病原菌。本研究证实，CASP4缺陷型巨噬细胞在受洋葱伯克霍尔德菌感染后，自噬体形成存在缺陷。CASP4的缺失会导致小GTP酶RAB7积累，降低洋葱伯克霍尔德菌与LC3及酸性区室的共定位水平，并伴随体外（in vitro）及体内（in vivo）环境下细菌增殖增强。综上，本研究数据揭示了CASP4在响应洋葱伯克霍尔德菌感染时调控自噬的全新功能。