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Aspergillus fumigatus Hsp90 interacts with the main components of the cell wall integrity pathway and cooperates in heat shock and cell wall stress adaptation
Cellular Microbiology ( IF 3.4 ) Pub Date : 2020-10-03 , DOI: 10.1111/cmi.13273
Marina Campos Rocha 1 , Karine Minari 1, 2 , João Henrique Tadini Marilhano Fabri 1 , Joshua D Kerkaert 3 , Lisandra Marques Gava 1 , Anderson Ferreira da Cunha 1 , Robert A Cramer 3 , Júlio César Borges 2 , Iran Malavazi 1
Affiliation  

The initiation of Aspergillus fumigatus infection occurs via dormant conidia deposition into the airways. Therefore, conidial germination and subsequent hyphal extension and growth occur in a sustained heat shock (HS) environment promoted by the host. The cell wall integrity pathway (CWIP) and the essential eukaryotic chaperone Hsp90 are critical for fungi to survive HS. Although A. fumigatus is a thermophilic fungus, the mechanisms underpinning the HS response are not thoroughly described and important to define its role in pathogenesis, virulence and antifungal drug responses. Here, we investigate the contribution of the CWIP in A. fumigatus thermotolerance. We observed that the CWIP components PkcA, MpkA and RlmA are Hsp90 clients and that a PkcAG579R mutation abolishes this interaction. PkcAG579R also abolishes MpkA activation in the short‐term response to HS. Biochemical and biophysical analyses indicated that Hsp90 is a dimeric functional ATPase, which has a higher affinity for ADP than ATP and prevents MpkA aggregation in vitro. Our data suggest that the CWIP is constitutively required for A. fumigatus to cope with the temperature increase found in the mammalian lung environment, emphasising the importance of this pathway in supporting thermotolerance and cell wall integrity.

中文翻译:

烟曲霉Hsp90与细胞壁完整性通路的主要成分相互作用,协同热休克和细胞壁应激适应

烟曲霉感染的开始是通过休眠的分生孢子沉积到气道中发生的。因此,分生孢子萌发和随后的菌丝延伸和生长发生在宿主促进的持续热休克(HS)环境中。细胞壁完整性通路 (CWIP) 和必需的真核伴侣蛋白 Hsp90 对于真菌在 HS 中存活至关重要。虽然A. fumigatus是一种嗜热真菌,但支持 HS 反应的机制尚未得到彻底描述,并且对于确定其在发病机制、毒力和抗真菌药物反应中的作用很重要。在这里,我们研究了 CWIP 在A. fumigatus耐热性中的贡献。我们观察到 CWIP 组件 PkcA、MpkA 和 RlmA 是 Hsp90 客户端,而 PkcAG579R突变消除了这种相互作用。PkcA G579R还消除了对 HS 的短期反应中的 MpkA 激活。生化和生物物理分析表明,Hsp90 是一种二聚体功能性 ATP 酶,它对 ADP 的亲和力高于 ATP,并在体外阻止 MpkA 聚集。我们的数据表明 CWIP 是A. fumigatus应对哺乳动物肺环境中发现的温度升高所必需的,强调了该途径在支持耐热性和细胞壁完整性方面的重要性。
更新日期:2020-10-03
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