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Mutual independence of alkaline‐ and calcium‐mediated signalling in Aspergillus fumigatus refutes the existence of a conserved druggable signalling nexus
Author(s) -
Loss Omar,
Bertuzzi Margherita,
Yan Yu,
Fedorova Natalie,
McCann Bethany L.,
ArmstrongJames Darius,
Espeso Eduardo A.,
Read Nick D.,
Nierman William C.,
Bignell Elaine M.
Publication year - 2017
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13840
Subject(s) - biology , calcium , calcineurin , calcium signaling , aspergillus fumigatus , biochemistry , microbiology and biotechnology , transcription factor , signal transduction , chemistry , gene , medicine , surgery , organic chemistry , transplantation
Summary Functional coupling of calcium‐ and alkaline responsive signalling occurs in multiple fungi to afford efficient cation homeostasis. Host microenvironments exert alkaline stress and potentially toxic concentrations of Ca 2+ , such that highly conserved regulators of both calcium‐ (Crz) and pH‐ (PacC/Rim101) responsive signalling are crucial for fungal pathogenicity. Drugs targeting calcineurin are potent antifungal agents but also perturb human immunity thereby negating their use as anti‐infectives, abrogation of alkaline signalling has, therefore, been postulated as an adjunctive antifungal strategy. We examined the interdependency of pH‐ and calcium‐mediated signalling in Aspergillus fumigatus and found that calcium chelation severely impedes hyphal growth indicating a critical requirement for this ion independently of ambient pH. Transcriptomic responses to alkaline pH or calcium excess exhibited minimal similarity. Mutants lacking calcineurin, or its client CrzA, displayed normal alkaline tolerance and nuclear translocation of CrzA was unaffected by ambient pH. Expression of a highly conserved, alkaline‐regulated, sodium ATPase was tolerant of genetic or chemical perturbations of calcium‐mediated signalling, but abolished in null mutants of the pH‐responsive transcription factor PacC, and PacC proteolytic processing occurred normally during calcium excess. Taken together our data demonstrate that in A . fumigatus the regulatory hierarchy governing alkaline tolerance circumvents calcineurin signalling.