Cited 32 times since 2017 (3.9 per year) source: EuropePMC Cell host & microbe, Volume 21, Issue 5, 1 1 2017, Pages 637-649.e6 Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection. Pandey A, Ding SL, Qin QM, Gupta R, Gomez G, Lin F, Feng X, Fachini da Costa L, Chaki SP, Katepalli M, Case ED, van Schaik EJ, Sidiq T, Khalaf O, Arenas A, Kobayashi KS, Samuel JE, Rivera GM, Alaniz RC, Sze SH, Qian X, Brown WJ, Rice-Ficht A, Russell WK, Ficht TA, de Figueiredo P
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.
