RgsA Attenuates the PKA Signaling, Stress Response, and Virulence in the Human Opportunistic Pathogen Aspergillus fumigatus
RgsA Attenuates the PKA Signaling, Stress Response, and Virulence in the Human Opportunistic Pathogen Aspergillus fumigatus
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DOI：
10.3390/ijms20225628
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Shin, Kwang-Soo
中科院分区：
文献类型：
--
作者：
Lwin, Hnin Phyu;Choi, Yong-Ho;Shin, Kwang-Soo
G蛋白信号调节蛋白（Regulator of G-protein signaling，RGS）在异源三聚体G蛋白信号通路的上游调控中发挥重要作用。在人类机会致病真菌烟曲霉的基因组中，存在六个RGS蛋白编码基因。为了表征预测编码具有RGS结构域的蛋白质的rgsA基因，我们产生了rgsA无效突变体并观察突变体的表型。rgsA的缺失（Delta）导致在固体和液体培养条件下径向生长增加和无性孢子形成增强。因此，转录水平的关键无性发育调节abaA，brlA，和wetA的三角洲rgsA突变体中升高。此外，Delta rgsA在不存在碳源的情况下导致孢子萌发率升高。cAMP依赖性蛋白激酶A（PKA）的活性和编码PKA信号传导元件的基因的mRNA水平被Delta rgsA升高。此外，与应激反应信号相关的基因的mRNA水平随着rgsA的缺乏而增加，并且Delta rgsA孢子表现出对氧化应激的耐受性增强。比较转录组学分析表明，三角洲rgsA突变体表现出较高的mRNA水平的胶毒素（GT）生物合成基因。因此，rgsA无效突变体在小鼠中表现出增加的GT产生和升高的毒力。相反，编码葡聚糖降解酶的大多数基因被Delta rgsA下调，并且内切葡聚糖酶活性降低。总之，RgsA发挥多种作用，控制生长，发育，应激反应，毒力和外部聚合物降解-可能通过减弱PKA信号传导。
The regulator of G-protein signaling (RGS) proteins play an important role in upstream control of heterotrimeric G-protein signaling pathways. In the genome of the human opportunistic pathogenic fungus Aspergillus fumigatus, six RGS protein-encoding genes are present. To characterize the rgsA gene predicted to encode a protein with an RGS domain, we generated an rgsA null mutant and observed the phenotypes of the mutant. The deletion (Delta) of rgsA resulted in increased radial growth and enhanced asexual sporulation in both solid and liquid culture conditions. Accordingly, transcripts levels of the key asexual developmental regulators abaA, brlA, and wetA are elevated in the Delta rgsA mutant. Moreover, Delta rgsA resulted in elevated spore germination rates in the absence of a carbon source. The activity of cAMP-dependent protein kinase A (PKA) and mRNA levels of genes encoding PKA signaling elements are elevated by Delta rgsA. In addition, mRNA levels of genes associated with stress-response signaling increased with the lack of rgsA, and the Delta rgsA spores showed enhanced tolerance against oxidative stressors. Comparative transcriptomic analyses revealed that the Delta rgsA mutant showed higher mRNA levels of gliotoxin (GT) biosynthetic genes. Accordingly, the rgsA null mutant exhibited increased production of GT and elevated virulence in the mouse. Conversely, the majority of genes encoding glucan degrading enzymes were down-regulated by Delta rgsA, and endoglucanase activities were reduced. In summary, RgsA plays multiple roles, governing growth, development, stress responses, virulence, and external polymer degradation-likely by attenuating PKA signaling.