The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans.
The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans.
复制标题
DOI：
10.1371/journal.ppat.1000889
复制
发表时间：
2010-05-13
期刊：
影响因子：
6.7
通讯作者：
Kuchler K
中科院分区：
文献类型：
--
作者：
Hnisz D;Majer O;Frohner IE;Komnenovic V;Kuchler K
白色念珠菌与其他多形真菌病原体一样，能够在单酵母样细胞和多细胞丝状体之间进行可逆转变。这种形态发生过程一直被认为是一个关键的真菌毒力因子。在这里，我们确定了进化上保守的Set 3/Hos 2组蛋白脱乙酰酶复合物（Set 3C）作为一个重要的阻遏物的酵母丝过渡。缺乏Set 3C核心成分的细胞能够维持所有发育阶段，但由于过度活跃的cAMP/蛋白激酶A信号通路，对细丝诱导信号高度敏感。值得注意的是，体内毒力需要Set 3C介导的表达控制，因为set 3 Δ/Δ细胞在全身感染的小鼠模型中显示出强烈减弱的毒力。重要的是，组蛋白脱乙酰酶活性的抑制，通过抑制素A专门phenocopies的情况下，一个功能性的Set 3C，但不是任何其他组蛋白脱乙酰酶基因。因此，我们的工作支持一个范例，操纵形态发生在C。白念珠菌通过替代抗真菌治疗策略。 白色念珠菌是引起免疫功能低下个体疾病的最普遍的人类真菌病原体。许多其他微生物病原体共有的一个关键毒力因子是其在单细胞和丝状形式之间进行形态发生转变的能力，这与宿主免疫系统有差异地相互作用。形态发生在C.白念珠菌的生长受多种信号通路控制，其中蛋白激酶A（PKA）营养感应通路是至关重要的。在这里，我们确定了一个保守的组蛋白去乙酰化酶复合物（Set 3C）作为PKA信号传导的关键负调节因子的作用，控制形态发生和毒力。Set 3C组蛋白脱乙酰酶复合物的遗传去除导致细胞在体外和体内均超细丝化，并触发PKA信号传导的激活。此外，缺乏Set 3的细胞在小鼠感染模型中显示出强烈减弱的毒力。这些结果提供了新的见解染色质修饰和信号转导途径的相互作用，作为例证的控制形态的多形真菌。此外，我们的工作建立了组蛋白脱乙酰酶作为抗真菌药物发现的潜在新靶点，以改善对抗危及生命的真菌感染的治疗方法。
Candida albicans, like other pleiomorphic fungal pathogens, is able to undergo a reversible transition between single yeast-like cells and multicellular filaments. This morphogenetic process has long been considered as a key fungal virulence factor. Here, we identify the evolutionarily conserved Set3/Hos2 histone deacetylase complex (Set3C) as a crucial repressor of the yeast-to-filament transition. Cells lacking core components of the Set3C are able to maintain all developmental phases, but are hypersusceptible to filamentation-inducing signals, because of a hyperactive cAMP/Protein Kinase A signaling pathway. Strikingly, Set3C-mediated control of filamentation is required for virulence in vivo, since set3Δ/Δ cells display strongly attenuated virulence in a mouse model of systemic infection. Importantly, the inhibition of histone deacetylase activity by trichostatin A exclusively phenocopies the absence of a functional Set3C, but not of any other histone deacetylase gene. Hence, our work supports a paradigm for manipulating morphogenesis in C. albicans through alternative antifungal therapeutic strategies. Candida albicans is the most prevalent human fungal pathogen causing disease in immunocompromised individuals. One key virulence factor, shared by many other microbial pathogens, is its ability to undergo morphogenetic transitions between unicellular and filamentous forms, which interact differentially with the host immune system. Morphogenesis in C. albicans is controlled by several signaling pathways, of which the Protein Kinase A (PKA) nutrient sensing pathway is of pivotal importance. Here, we identify a role for a conserved histone deacetylase complex (Set3C) as a key negative regulator of PKA signaling, controlling both morphogenesis and virulence. The genetic removal of the Set3C histone deacetylase complex causes cells to hyperfilament both in vitro and in vivo, and triggers the activation of PKA signaling. Moreover, cells lacking Set3 show strongly attenuated virulence in a mouse infection model. These results provide novel insights about the interplay of chromatin modification and signaling pathways, as exemplified by the control of morphogenesis of pleiomorphic fungi. Furthermore, our work establishes histone deacetylases as potential novel targets for antifungal drug discovery to improve therapeutic approaches combating life-threatening fungal infections.
登录
查看更多内容
影响因子：
3.6
作者：
Hnisz D;Schwarzmüller T;Kuchler K
通讯作者：
Kuchler K
影响因子：
56.9
作者：
Domergue, R;Castaño, I;Cormack, BP
通讯作者：
Cormack, BP
影响因子：
4.8
作者：
Castilla, R;Passeron, S;Cantore, ML
通讯作者：
Cantore, ML
影响因子：
64.5
作者：
Kim T;Buratowski S
通讯作者：
Buratowski S
DOI：
10.1073/pnas.0605270103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Huang, Guanghua;Wang, Huafeng;Liu, Haoping
通讯作者：
Liu, Haoping