Bakowski Malina A, Desjardins Christopher A, Smelkinson Margery G, Dunbar Tiffany L, Lopez-Moyado Isaac F, Rifkin Scott A, Cuomo Christina A, Troemel Emily R
Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, California, United States of America.
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
PLoS Pathog. 2014 Jun 19;10(6):e1004200. doi: 10.1371/journal.ppat.1004200. eCollection 2014 Jun.
Microsporidia comprise a phylum of over 1400 species of obligate intracellular pathogens that can infect almost all animals, but little is known about the host response to these parasites. Here we use the whole-animal host C. elegans to show an in vivo role for ubiquitin-mediated response to the microsporidian species Nematocida parisii, as well to the Orsay virus, another natural intracellular pathogen of C. elegans. We analyze gene expression of C. elegans in response to N. parisii, and find that it is similar to response to viral infection. Notably, we find an upregulation of SCF ubiquitin ligase components, such as the cullin ortholog cul-6, which we show is important for ubiquitin targeting of N. parisii cells in the intestine. We show that ubiquitylation components, the proteasome, and the autophagy pathway are all important for defense against N. parisii infection. We also find that SCF ligase components like cul-6 promote defense against viral infection, where they have a more robust role than against N. parisii infection. This difference may be due to suppression of the host ubiquitylation system by N. parisii: when N. parisii is crippled by anti-microsporidia drugs, the host can more effectively target pathogen cells for ubiquitylation. Intriguingly, inhibition of the ubiquitin-proteasome system (UPS) increases expression of infection-upregulated SCF ligase components, indicating that a trigger for transcriptional response to intracellular infection by N. parisii and virus may be perturbation of the UPS. Altogether, our results demonstrate an in vivo role for ubiquitin-mediated defense against microsporidian and viral infections in C. elegans.
微孢子虫是一个包含1400多种专性细胞内病原体的门，几乎可以感染所有动物，但人们对宿主对这些寄生虫的反应知之甚少。在这里，我们使用全动物宿主秀丽隐杆线虫来展示泛素介导的对微孢子虫物种巴黎嗜线虫致病杆菌的反应在体内的作用，以及对奥赛病毒（秀丽隐杆线虫的另一种天然细胞内病原体）的反应。我们分析了秀丽隐杆线虫对巴黎嗜线虫致病杆菌的反应中的基因表达，发现它与对病毒感染的反应相似。值得注意的是，我们发现SCF泛素连接酶成分上调，例如cullin直系同源物cul-6，我们证明它对于肠道中巴黎嗜线虫致病杆菌细胞的泛素靶向很重要。我们表明泛素化成分、蛋白酶体和自噬途径对于抵御巴黎嗜线虫致病杆菌感染都很重要。我们还发现像cul-6这样的SCF连接酶成分促进对病毒感染的防御，它们在这方面的作用比对巴黎嗜线虫致病杆菌感染的作用更强。这种差异可能是由于巴黎嗜线虫致病杆菌对宿主泛素化系统的抑制：当巴黎嗜线虫致病杆菌被抗微孢子虫药物削弱时，宿主可以更有效地将病原体细胞作为泛素化的靶点。有趣的是，抑制泛素-蛋白酶体系统（UPS）会增加感染上调的SCF连接酶成分的表达，这表明对巴黎嗜线虫致病杆菌和病毒细胞内感染的转录反应的触发因素可能是UPS的扰动。总之，我们的结果证明了泛素介导的防御在秀丽隐杆线虫抵抗微孢子虫和病毒感染中的体内作用。
