Mutual independence of alkaline- and calcium-mediated signalling in Aspergillus fumigatus refutes the existence of a conserved druggable signalling nexus.
Mutual independence of alkaline- and calcium-mediated signalling in Aspergillus fumigatus refutes the existence of a conserved druggable signalling nexus.
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DOI：
10.1111/mmi.13840
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发表时间：
2017-12
影响因子：
3.6
通讯作者：
Bignell EM
中科院分区：
文献类型：
--
作者：
Loss O;Bertuzzi M;Yan Y;Fedorova N;McCann BL;Armstrong-James D;Espeso EA;Read ND;Nierman WC;Bignell EM
在多种真菌中，钙和碱反应信号的功能偶联可以提供有效的阳离子稳态。宿主微环境施加碱性胁迫和潜在毒性浓度的Ca2+，因此高度保守的钙离子（Crz）和pH离子（PacC/Rim101）应答信号调节因子对真菌致病性至关重要。以钙调磷酸酶为靶点的药物是有效的抗真菌药物，但也会干扰人体免疫，从而使其作为抗感染药物的作用失效，因此，取消碱性信号被认为是一种辅助的抗真菌策略。我们研究了烟曲霉中pH和钙介导信号的相互依赖性，发现钙螯合严重阻碍菌丝生长，表明钙离子的关键需求独立于环境pH。对碱性pH或钙过量的转录组反应表现出最小的相似性。缺乏钙调神经磷酸酶或其客户端CrzA的突变体表现出正常的碱性耐受性，CrzA的核易位不受环境pH的影响。高度保守的碱性调节atp酶钠的表达可以耐受钙介导的信号传导的遗传或化学扰动，但在pH响应转录因子PacC的零突变体中被取消，PacC蛋白水解加工在钙过量时正常发生。综上所述，我们的数据表明，在烟曲霉中，控制碱性耐受性的调节等级绕过了钙调神经磷酸酶信号传导。
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 Ca2+, 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.
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影响因子：
3.6
作者：
Bussink HJ;Bignell EM;Múnera-Huertas T;Lucena-Agell D;Scazzocchio C;Espeso EA;Bertuzzi M;Rudnicka J;Negrete-Urtasun S;Peñas-Parilla MM;Rainbow L;Peñalva MÁ;Arst HN Jr;Tilburn J
通讯作者：
Tilburn J
影响因子：
3
作者：
Findon, Helen;Calcagno-Pizarelli, Ana-Maria;Martinez, Jose L.;Spielvogel, Anja;Markina-Inarrairaegui, Ane;Indrakumar, Tanya;Ramos, Jose;Penalva, Miguel A.;Espeso, Eduardo A.;Arst, Herbert N., Jr.
通讯作者：
Arst, Herbert N., Jr.
影响因子：
3.1
作者：
Davis, D;Edwards, JE;Ibrahim, AS
通讯作者：
Ibrahim, AS
影响因子：
5.3
作者：
Davis, D;Wilson, RB;Mitchell, AP
通讯作者：
Mitchell, AP
影响因子：
3.1
作者：
Amich, Jorge;Leal, Fernando;Calera, Jose A.
通讯作者：
Calera, Jose A.