Pandey Aseem, Ding Sheng Li, Qin Qing-Ming, Gupta Rahul, Gomez Gabriel, Lin Furong, Feng Xuehuan, Fachini da Costa Luciana, Chaki Sankar P, Katepalli Madhu, Case Elizabeth D, van Schaik Erin J, Sidiq Tabasum, Khalaf Omar, Arenas Angela, Kobayashi Koichi S, Samuel James E, Rivera Gonzalo M, Alaniz Robert C, Sze Sing-Hoi, Qian Xiaoning, Brown William J, Rice-Ficht Allison, Russell William K, Ficht Thomas A, de Figueiredo Paul
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, Texas 77843, USA; Norman Borlaug Center, Texas A&M University, College Station, Texas 77843, USA; Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843, USA.
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, Texas 77843, USA; Norman Borlaug Center, Texas A&M University, College Station, Texas 77843, USA; Department of Plant Pathology, College of Plant Protection, Henan Agricultural University, Zhengzhou 450002, Henan, China.
Cell Host Microbe. 2017 May 10;21(5):637-649.e6. doi: 10.1016/j.chom.2017.04.008.
Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins that are differentially phosphorylated following fungal ingestion by macrophages, thereby indicating global reprogramming of host kinase signaling. Notably, phagocytosis of the pathogen activates the host autophagy initiation complex (AIC) and the upstream regulatory components LKB1 and AMPKα, which regulate autophagy induction through their kinase activities. Deletion of Prkaa1, the gene encoding AMPKα1, in monocytes results in resistance to fungal colonization of mice. Finally, the recruitment of AIC components to nascent Cryptococcus-containing vacuoles (CnCVs) regulates the intracellular trafficking and replication of the pathogen. These findings demonstrate that host AIC regulatory networks confer susceptibility to infection and establish a proteomic resource for elucidating host mechanisms that regulate fungal intracellular parasitism.
新型隐球菌（Cn）是一种致命的真菌病原体，其细胞内生存方式对毒力至关重要。控制真菌吞噬和复制的宿主机制仍不清楚。在此，我们对宿主对隐球菌感染的反应进行了全面的磷酸化蛋白质组分析。我们的分析揭示了大量不同的宿主蛋白，这些蛋白在巨噬细胞吞噬真菌后发生了差异磷酸化，从而表明宿主激酶信号发生了全面重编程。值得注意的是，病原体的吞噬激活了宿主自噬起始复合物（AIC）以及上游调节成分LKB1和AMPKα，它们通过激酶活性调节自噬诱导。单核细胞中编码AMPKα1的基因Prkaa1的缺失导致小鼠对真菌定植产生抗性。最后，AIC成分募集到新生的含新型隐球菌液泡（CnCVs）中，调节病原体的细胞内运输和复制。这些发现表明宿主AIC调节网络赋予了感染易感性，并建立了一个蛋白质组学资源，用于阐明调节真菌细胞内寄生的宿主机制。
