Departments of Microbiology, Immunology and Infectious Diseases, Calgary, AB, Canada.
Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
Mucosal Immunol. 2021 Sep;14(5):1038-1054. doi: 10.1038/s41385-021-00408-4. Epub 2021 May 7.
The mechanism whereby Entamoeba histolytica (Eh) binding with macrophages at the intercellular junction triggers aggressive pro-inflammatory responses in disease pathogenesis is not well understood. The host intracellular protein degradation process autophagy and its regulatory proteins are involved in maintenance of cellular homeostasis and excessive inflammatory responses. In this study we unraveled how Eh hijacks the autophagy process in macrophages to dysregulate pro-inflammatory responses. Direct contact of live Eh with macrophages activated caspase-6 that induced rapid proteolytic degradation of the autophagy ATG16L1 protein complex independent of NLRP3 inflammasome and caspase-3/8 activation. Crohn's disease susceptible ATG16L1 T300A variant was highly susceptible to Eh-mediated degradation that augmented pro-inflammatory cytokines in mice. Quantitative proteomics revealed downregulation of autophagy and vesicle-mediated transport and upregulation of cysteine-type endopeptidase pathways in response to Eh. We conclude during Eh-macrophage outside-in signaling, ATG16L1 protein complex plays an overlooked regulatory role in shaping the pro-inflammatory landscape in amebiasis.
溶组织内阿米巴（Eh）与细胞间连接的巨噬细胞结合，触发疾病发病机制中侵袭性促炎反应的机制尚不清楚。宿主细胞内蛋白降解过程自噬及其调节蛋白参与维持细胞内稳态和过度炎症反应。在这项研究中，我们揭示了 Eh 如何劫持巨噬细胞中的自噬过程来扰乱促炎反应。活 Eh 与巨噬细胞的直接接触激活了半胱天冬酶-6，该酶诱导自噬 ATG16L1 蛋白复合物的快速蛋白水解降解，而不依赖 NLRP3 炎性小体和半胱天冬酶-3/8 的激活。易患克罗恩病的 ATG16L1 T300A 变体极易受到 Eh 介导的降解，从而增加了小鼠中的促炎细胞因子。定量蛋白质组学显示，自噬和囊泡介导的运输下调，以及半胱氨酸内肽酶途径上调，以响应 Eh。我们的结论是，在 Eh-巨噬细胞外向信号转导过程中，ATG16L1 蛋白复合物在塑造阿米巴病中的促炎景观中起着被忽视的调节作用。
