期刊
VIRULENCE
卷 8, 期 8, 页码 1833-1848出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/21505594.2017.1385692
关键词
Cryptococcus neoformans; inositol pyrophosphate; PP-IP5; IP7; inositol polyphosphate kinase; virulence; molecular fungal pathogenesis; mouse model; meningitis; cell wall
资金
- National Health and Medical Research Council of Australia (NHMRC) project [APP1058779_Djordjevic]
- Australian Postgraduate Award
- Westmead Institute for Medical Research (WIMR) Career Development award
- Medical Research Council (MRC) [MC_UU_1201814]
- NHMRC
- Sydney Medical School Foundation
- Medical Research Council [MC_UU_00012/4, MC_UU_12018/4, MC_U122680443] Funding Source: researchfish
- MRC [MC_UU_12018/4, MC_UU_00012/4, MC_U122680443] Funding Source: UKRI
We previously identified a series of inositol polyphosphate kinases (IPKs), Arg1, Ipk1, Kcs1 and Asp1, in the opportunistic fungal pathogen Cryptococcus neoformans. Using gene deletion analysis, we characterized Arg1, Ipk1 and Kcs1 and showed that they act sequentially to convert IP3 to PP-IP5 (IP7), a key metabolite promoting stress tolerance, metabolic adaptation and fungal dissemination to the brain. We have now directly characterized the enzymatic activity of Arg1, demonstrating that it is a dual specificity (IP3/IP4) kinase producing IP5. We showed previously that IP5 is further phosphorylated by Ipk1 to produce IP6, which is a substrate for the synthesis of PP-IP5 by Kcs1. Phenotypic comparison of the arg1 Delta and kcs1 Delta deletion mutants (both PP-IP5-deficient) reveals that arg1 Delta has the most deleterious phenotype: while PP-IP5 is essential for metabolic and stress adaptation in both mutant strains, PP-IP5 is dispensable for virulence-associated functions such as capsule production, cell wall organization, and normal N-linked mannosylation of the virulence factor, phospholipase B1, as these phenotypes were defective only in arg1 Delta. The more deleterious arg1 Delta phenotype correlated with a higher rate of arg1 Delta phagocytosis by human peripheral blood monocytes and rapid arg1 Delta clearance from lung in a mouse model. This observation is in contrast to kcs1 Delta, which we previously reported establishes a chronic, confined lung infection. In summary, we show that Arg1 is the most crucial IPK for cryptococcal virulence, conveying PP-IP5-dependent and novel PP-IP5-independent functions.
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