دورية أكاديمية
أعرض في EDS

Arg1 from Cryptococcus neoformans lacks PI3 kinase activity and conveys virulence roles via its IP 3-4 kinase activity.

التفاصيل البيبلوغرافية
العنوان: Arg1 from Cryptococcus neoformans lacks PI3 kinase activity and conveys virulence roles via its IP 3-4 kinase activity.
المؤلفون: Desmarini D; Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Sydney, Australia.; Faculty of Medicine and Health, Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia., Liu G; Institute of Organic Chemistry, University of Freiburg, Freiburg im Breisgau, Germany.; Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany., Jessen H; Institute of Organic Chemistry, University of Freiburg, Freiburg im Breisgau, Germany.; Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany., Bowring B; Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Sydney, Australia.; Faculty of Medicine and Health, Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia., Connolly A; Sydney Mass Spectrometry, University of Sydney, Sydney, Australia., Crossett B; Sydney Mass Spectrometry, University of Sydney, Sydney, Australia., Djordjevic JT; Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Sydney, Australia.; Faculty of Medicine and Health, Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia.; Westmead Hospital, Western Sydney Local Health District, Sydney, Australia.
المصدر: MBio [mBio] 2024 Jun 12; Vol. 15 (6), pp. e0060824. Date of Electronic Publication: 2024 May 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Society for Microbiology
مواضيع طبية MeSH: Cryptococcus neoformans*/genetics , Cryptococcus neoformans*/pathogenicity , Cryptococcus neoformans*/enzymology, Virulence ; Animals ; Cryptococcosis/microbiology ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Virulence Factors/genetics ; Virulence Factors/metabolism
مستخلص: Inositol tris/tetrakis phosphate kinases (IP 3-4 K) in the human fungal priority pathogens, Cryptococcus neoformans ( Cn Arg1) and Candida albicans ( Ca Ipk2), convey numerous virulence functions, yet it is not known whether the IP 3-4 K catalytic activity or a scaffolding role is responsible. We therefore generated a C. neoformans strain with a non-functional kinase, referred to as the dead-kinase (dk) Cn Arg1 strain (dkArg1). We verified that, although dk ARG1 cDNA cloned from this strain produced a protein with the expected molecular weight, dkArg1 was catalytically inactive with no IP 3-4 K activity. Using recombinant Cn Arg1 and Ca Ipk2 , we confirmed that, unlike the IP 3-4 K homologs in humans and Saccharomyces cerevisiae , Cn Arg1 and Ca Ipk2 do not phosphorylate the lipid-based substrate, phosphatidylinositol 4,5-bisphosphate, and therefore do not function as class I PI3Ks. Inositol polyphosphate profiling using capillary electrophoresis-electrospray ionization-mass spectrometry revealed that IP 3 conversion is blocked in the dkArg1 and ARG1 deletion ( Cnarg1 Δ) strains and that 1-IP 7 and a recently discovered isomer (4/6-IP 7 ) are made by wild-type C. neoformans . Importantly, the dkArg1 and Cnarg1 Δ strains had similar virulence defects, including suppressed growth at 37°C, melanization, capsule production, and phosphate starvation response, and were avirulent in an insect model, confirming that virulence is dependent on IP 3-4 K catalytic activity. Our data also implicate the dkArg1 scaffold in transcriptional regulation of arginine metabolism but via a different mechanism to S. cerevisiae since Cn Arg1 is dispensable for growth on different nitrogen sources. IP 3-4 K catalytic activity therefore plays a dominant role in fungal virulence, and IPK pathway function has diverged in fungal pathogens.IMPORTANCEThe World Health Organization has emphasized the urgent need for global action in tackling the high morbidity and mortality rates stemming from invasive fungal infections, which are exacerbated by the limited variety and compromised effectiveness of available drug classes. Fungal IP 3-4 K is a promising target for new therapy, as it is critical for promoting virulence of the human fungal priority pathogens, Cryptococcus neoformans and Candida albicans , and impacts numerous functions, including cell wall integrity. This contrasts to current therapies, which only target a single function. IP 3-4 K enzymes exert their effect through their inositol polyphosphate products or via the protein scaffold. Here, we confirm that the IP 3-4 K catalytic activity of Cn Arg1 promotes all virulence traits in C. neoformans that are attenuated by ARG1 deletion , reinforcing our ongoing efforts to find inositol polyphosphate effector proteins and to create inhibitors targeting the IP 3-4 K catalytic site, as a new antifungal drug class.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: 1183939 DHAC | National Health and Medical Research Council (NHMRC); 390939984 Deutsche Forschungsgemeinschaft (DFG)
فهرسة مساهمة: Keywords: Candida albicans; Cryptococcus neoformans; IP3-4K; PI3K; fungi; inositol polyphosphate kinase; mycology; virulence
المشرفين على المادة: 0 (Fungal Proteins)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
0 (Virulence Factors)
تواريخ الأحداث: Date Created: 20240514 Date Completed: 20240612 Latest Revision: 20240714
رمز التحديث: 20240714
مُعرف محوري في PubMed: PMC11237472
DOI: 10.1128/mbio.00608-24
PMID: 38742909
قاعدة البيانات: MEDLINE
الوصف
تدمد:2150-7511
DOI:10.1128/mbio.00608-24