Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control Mycobacterium tuberculosis Infection in Macrophages.
Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control Mycobacterium tuberculosis Infection in Macrophages.
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DOI：
10.1128/mbio.01871-20
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Watson RO
中科院分区：
文献类型：
--
作者：
Bell SL;Lopez KL;Cox JS;Patrick KL;Watson RO
结核分枝杆菌（Mtb）是世界上最致命的传染病之一。感染后，Mtb被巨噬细胞吞噬，并使用其毒力相关的ESX-1分泌系统来调节宿主细胞。我们先前表明，ESX-1分泌系统干扰含Mtb的吞噬体，并且细胞内Mtb的群体（约30%）用泛素标记并靶向选择性自噬。然而，我们对巨噬细胞如何感知和响应受损的含结核杆菌吞噬体的理解仍然不完整。在这里，我们证明了几种称为半乳糖凝集素的细胞溶质聚糖结合蛋白识别含结核分枝杆菌的吞噬体;在巨噬细胞系和原代巨噬细胞中，半乳糖凝集素-3，8和9都被招募到与选择性自噬标记物（泛素，p62和LC 3）共定位的相同结核分枝杆菌群体中。为了测试半乳糖凝集素是否是控制巨噬细胞中Mtb复制所必需的，我们产生了CRISPR/Cas9敲除，发现半乳糖凝集素-8-/-和半乳糖凝集素-3/8/9-/-巨噬细胞在靶向Mtb以选择性自噬和控制复制方面存在类似缺陷。这表明半乳糖凝集素-8在抗Mtb自噬中发挥独特作用。在研究半乳糖凝集素-8的作用时，我们鉴定了半乳糖凝集素-8与选择性自噬衔接子TAX 1BP 1之间的新型特异性相互作用，并发现这种半乳糖凝集素-8/TAX1BP1相互作用对于巨噬细胞有效靶向Mtb进行选择性自噬是必需的。值得注意的是，过表达半乳糖凝集素-8增加了Mtb对自噬的靶向，并限制了Mtb的复制。总之，这些数据表明，虽然几种半乳糖凝集素能够识别受损的含结核分枝杆菌的吞噬体，但半乳糖凝集素-8在招募下游自噬机制中发挥着特殊作用，并可能代表宿主定向结核病治疗的有希望的靶点。
Mycobacterium tuberculosis (Mtb) causes one of the deadliest infectious diseases worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell. We showed previously that the ESX-1 secretion system perturbs the Mtb-containing phagosome, and a population (∼30%) of intracellular Mtb is tagged with ubiquitin and targeted to selective autophagy. However, our understanding of how macrophages sense and respond to damaged Mtb-containing phagosomes remains incomplete. Here, we demonstrate that several cytosolic glycan-binding proteins called galectins recognize Mtb-containing phagosomes; in macrophage cell lines and in primary macrophages, galectin-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers (ubiquitin, p62, and LC3). To test whether galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockouts and found that galectin-8−/− and galectin-3/8/9−/− macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication. This suggests galectin-8 plays a unique role in anti-Mtb autophagy. In investigating galectin-8's role, we identified a novel and specific interaction between galectin-8 and the selective autophagy adapter TAX1BP1 and found that this galectin-8/TAX1BP1 interaction was necessary for macrophages to efficiently target Mtb to selective autophagy. Remarkably, overexpressing galectin-8 increased targeting of Mtb to autophagy and limited Mtb replication. Taken together, these data demonstrate that while several galectins are capable of recognizing damaged Mtb-containing phagosomes, galectin-8 plays a privileged role in recruiting downstream autophagy machinery and may represent a promising target for host-directed tuberculosis therapies.