A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans.,PLoS Pathogens

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A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2019-12-06 , DOI: 10.1371/journal.ppat.1007823
Anaïs Burgain _{1,

2} , Émilie Pic ₁ , Laura Markey _{3,

4} , Faiza Tebbji ₁ , Carol A Kumamoto ₄ , Adnane Sellam _{1,

2,

5}

Affiliation

Inside the human host, the pathogenic yeast Candida albicans colonizes predominantly oxygen-poor niches such as the gastrointestinal and vaginal tracts, but also oxygen-rich environments such as cutaneous epithelial cells and oral mucosa. This suppleness requires an effective mechanism to reversibly reprogram the primary metabolism in response to oxygen variation. Here, we have uncovered that Snf5, a subunit of SWI/SNF chromatin remodeling complex, is a major transcriptional regulator that links oxygen status to the metabolic capacity of C. albicans. Snf5 and other subunits of SWI/SNF complex were required to activate genes of carbon utilization and other carbohydrates related process specifically under hypoxia. snf5 mutant exhibited an altered metabolome reflecting that SWI/SNF plays an essential role in maintaining metabolic homeostasis and carbon flux in C. albicans under hypoxia. Snf5 was necessary to activate the transcriptional program linked to both commensal and invasive growth. Accordingly, snf5 was unable to maintain its growth in the stomach, the cecum and the colon of mice. snf5 was also avirulent as it was unable to invade Galleria larvae or to cause damage to human enterocytes and murine macrophages. Among candidates of signaling pathways in which Snf5 might operate, phenotypic analysis revealed that mutants of Ras1-cAMP-PKA pathway, as well as mutants of Yak1 and Yck2 kinases exhibited a similar carbon flexibility phenotype as did snf5 under hypoxia. Genetic interaction analysis indicated that the adenylate cyclase Cyr1, a key component of the Ras1-cAMP pathway interacted genetically with Snf5. Our study yielded new insight into the oxygen-sensitive regulatory circuit that control metabolic flexibility, stress, commensalism and virulence in C. albicans.

中文翻译：

在真菌病原体白色念珠菌中控制缺氧代谢灵活性，共鸣和毒力的新型遗传电路。

在人类宿主内部，致病性酵母白色念珠菌主要定居在缺氧的环境中，例如胃肠道和阴道，但也定居在富氧的环境中，例如皮肤上皮细胞和口腔粘膜。这种柔软性需要一种有效的机制来响应氧气变化而可逆地重新编程主要的新陈代谢。在这里，我们发现SWI / SNF染色质重塑复合体的亚基Snf5是将氧状态与白色念珠菌的代谢能力联系起来的主要转录调节因子。需要Snf5和SWI / SNF复合体的其他亚基来激活碳利用和其他碳水化合物相关过程的基因，特别是在缺氧条件下。snf5突变体的代谢组发生了变化，这反映了SWI / SNF在缺氧条件下在白色念珠菌中维持代谢稳态和碳通量起着至关重要的作用。Snf5是激活与共生和侵袭性生长相关的转录程序所必需的。因此，snf5无法在小鼠的胃，盲肠和结肠中维持其生长。snf5也是无毒的，因为它不能侵入Galleria幼虫或不能破坏人的肠上皮细胞和鼠巨噬细胞。在Snf5可能起作用的信号传导途径的候选物中，表型分析显示Ras1-cAMP-PKA途径的突变体以及Yak1和Yck2激酶的突变体在缺氧条件下表现出与snf5相似的碳柔韧性表型。遗传相互作用分析表明，腺苷酸环化酶Cyr1，Ras1-cAMP途径的关键组成部分与Snf5进行了遗传相互作用。我们的研究对控制白念珠菌的代谢敏感性，应激，共鸣和毒力的氧敏感性调节回路产生了新的见解。

更新日期：2019-12-07

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