Hrk1 plays both Hog1-dependent and -independent roles in controlling stress response and antifungal drug resistance in Cryptococcus neoformans.
Hrk1 plays both Hog1-dependent and -independent roles in controlling stress response and antifungal drug resistance in Cryptococcus neoformans.
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DOI：
10.1371/journal.pone.0018769
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发表时间：
2011-04-13
期刊：
影响因子：
3.7
通讯作者：
Bahn YS
中科院分区：
文献类型：
--
作者：
Kim SY;Ko YJ;Jung KW;Strain A;Nielsen K;Bahn YS
HOG（高渗透压甘油反应）途径在控制应激反应、麦角固醇生物合成、毒力因子产生和导致致命性真菌性脑膜脑炎的新型隐球菌分化中起核心作用。最近对HOG通路的转录组分析发现了Hog1调节的基因（CNAG_00130.2），其编码推定的蛋白激酶，在酿酒酵母中与Rck1/2直向同源，在粟酒裂殖酵母中与Srk1直向同源。它的功能在C中是未知的。新人类本研究从功能上描述了Hrk 1在C.新人类北方印迹分析证实HRK 1的表达依赖于Hog 1 MAPK。与hog1 Δ突变体相似，hrk 1 Δ突变体对咯菌腈表现出几乎完全的抗性，咯菌腈通过HOG途径触发甘油生物合成。支持这一点，hrk1 Δ突变体显示细胞内甘油积累减少和细胞形态肿胀，以响应咯菌腈，进一步表明Hrk1在HOG通路下游起作用。然而，Hrk1似乎也有Hog1独立的功能。HRK1的突变不仅进一步增加了hog1 Δ突变体的对吡咯的敏感性，而且以不依赖于Erg11的方式抑制了hog1 Δ突变体对吡咯的耐药性。此外，与hog1 Δ突变体不同，Hrk1不参与荚膜生物合成。Hrk1与黑色素的产生有一定的关系，但与C.新人类这些结果表明，Hrk 1在应激、抗真菌药物敏感性和毒力因子的产生中起着Hog1依赖和非依赖的作用。新人类特别是，抑制Hrk1显著增加唑类药物敏感性的发现为联合抗真菌治疗提供了一种新的策略。
The HOG (High Osmolarity Glycerol response) pathway plays a central role in controlling stress response, ergosterol biosynthesis, virulence factor production, and differentiation of Cryptococcus neoformans, which causes fatal fungal meningoencephalitis. Recent transcriptome analysis of the HOG pathway discovered a Hog1-regulated gene (CNAG_00130.2), encoding a putative protein kinase orthologous to Rck1/2 in Saccharomyces cerevisiae and Srk1 in Schizosaccharomyces pombe. Its function is not known in C. neoformans. The present study functionally characterized the role of Hrk1 in C. neoformans. Northern blot analysis confirmed that HRK1 expression depends on the Hog1 MAPK. Similar to the hog1Δ mutant, the hrk1Δ mutant exhibited almost complete resistance to fludioxonil, which triggers glycerol biosynthesis via the HOG pathway. Supporting this, the hrk1Δ mutant showed reduced intracellular glycerol accumulation and swollen cell morphology in response to fludioxonil, further suggesting that Hrk1 works downstream of the HOG pathway. However, Hrk1 also appeared to have Hog1-independent functions. Mutation of HRK1 not only further increased osmosensitivity of the hog1Δ mutant, but also suppressed increased azole-resistance of the hog1Δ mutant in an Erg11-independent manner. Furthermore, unlike the hog1Δ mutant, Hrk1 was not involved in capsule biosynthesis. Hrk1 was slightly involved in melanin production but dispensable for virulence of C. neoformans. These findings suggest that Hrk1 plays both Hog1-dependent and –independent roles in stress and antifungal drug susceptibility and virulence factor production in C. neoformans. Particularly, the finding that inhibition of Hrk1 substantially increases azole drug susceptibility provides a novel strategy for combination antifungal therapy.
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