The Zn2Cys6-type transcription factor LeuB cross-links regulation of leucine biosynthesis and iron acquisition in Aspergillus fumigatus.
The Zn2Cys6-type transcription factor LeuB cross-links regulation of leucine biosynthesis and iron acquisition in Aspergillus fumigatus.
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Zn(2)Cys(6)型转录因子LeuB交联调节烟曲霉亮氨酸生物合成和铁获取
DOI：
10.1371/journal.pgen.1007762
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发表时间：
2018-10
期刊：
影响因子：
4.5
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Long N;Orasch T;Zhang S;Gao L;Xu X;Hortschansky P;Ye J;Zhang F;Xu K;Gsaller F;Straßburger M;Binder U;Heinekamp T;Brakhage AA;Haas H;Lu L
支链氨基酸（BCAA）和铁都是真核细胞必需的营养物质。此前，zn2cys6型转录因子Leu3/LeuB在酿酒酵母和芽曲霉BCAA生物合成和氮代谢的调控中发挥了至关重要的作用。在这项研究中，我们发现烟曲霉的同源物LeuB不仅参与BCAA的生物合成和氮代谢，还参与铁的获取，包括铁载体代谢。缺乏亮氨酸导致生长缺陷，可以通过补充亮氨酸或铁来治愈。此外，LeuB和HapX（一种适应铁饥饿所需的bZIP转录因子）同时失活，显著加剧了铁饥饿期间其中一种调节因子失活导致的生长缺陷。与BCAA和铁代谢的直接调节作用一致，研究发现，LeuB在体外和体内与BCAA生物合成、氮代谢和铁获取相关基因的启动子中结合系统发育保守的基序，并且是充分激活其表达所必需的。缺乏亮氨酸还会引起蛋白酶活性的激活和通过亮氨酸耗竭引起的自噬。此外，LeuB灭活可使烟曲霉对mellonella的毒力减弱。综上所述，本研究确定了BCCA生物合成、氮代谢和铁稳态以及蛋白质水解的直接交叉调节。对宿主生态位的适应是病原体的基本属性。本研究发现zn2cys6型转录因子LeuB交叉调控烟曲霉支链氨基酸生物合成、氮代谢、铁载体获取铁和蛋白酶体活性。在昆虫感染模型中，缺乏这种调控回路会损害毒力。哺乳动物既不表达zn2cys6型转录因子，也不具有产生支链氨基酸或铁载体的能力。因此，这种调节回路是真菌病原体对宿主生态位的特异性适应的范例。
Both branched-chain amino acids (BCAA) and iron are essential nutrients for eukaryotic cells. Previously, the Zn2Cys6-type transcription factor Leu3/LeuB was shown to play a crucial role in regulation of BCAA biosynthesis and nitrogen metabolism in Saccharomyces cerevisiae and Aspergillus nidulans. In this study, we found that the A. fumigatus homolog LeuB is involved in regulation of not only BCAA biosynthesis and nitrogen metabolism but also iron acquisition including siderophore metabolism. Lack of LeuB caused a growth defect, which was cured by supplementation with leucine or iron. Moreover, simultaneous inactivation of LeuB and HapX, a bZIP transcription factor required for adaptation to iron starvation, significantly aggravated the growth defect caused by inactivation of one of these regulators during iron starvation. In agreement with a direct role in regulation of both BCAA and iron metabolism, LeuB was found to bind to phylogenetically conserved motifs in promoters of genes involved in BCAA biosynthesis, nitrogen metabolism, and iron acquisition in vitro and in vivo, and was required for full activation of their expression. Lack of LeuB also caused activation of protease activity and autophagy via leucine depletion. Moreover, LeuB inactivation resulted in virulence attenuation of A. fumigatus in Galleria mellonella. Taken together, this study identified a previously uncharacterized direct cross-regulation of BCCA biosynthesis, nitrogen metabolism and iron homeostasis as well as proteolysis. Adaptation to the host niche is an essential attribute of pathogens. Here we found that the Zn2Cys6-type transcription factor LeuB cross-regulates branched-chain amino acid biosynthesis, nitrogen metabolism, iron acquisition via siderophores, and proteasome activity in the mold Aspergillus fumigatus. Lack of this regulatory circuit impaired virulence in an insect infection model. Mammals do neither express Zn2Cys6-type transcription factors nor have the capacity to produce branched-chain amino acids or siderophores. Consequently, this regulatory circuit is a paradigm for fungal pathogen-specific adaptation to the host niche.
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DOI：
10.15252/embj.201489468
发表时间：
2014-10-01
期刊：
The EMBO journal
影响因子：
--
作者：
Gsaller F;Hortschansky P;Beattie SR;Klammer V;Tuppatsch K;Lechner BE;Rietzschel N;Werner ER;Vogan AA;Chung D;Mühlenhoff U;Kato M;Cramer RA;Brakhage AA;Haas H
通讯作者：
Haas H
影响因子：
5.2
作者：
Fallon, John P.;Troy, Niamh;Kavanagh, Kevin
通讯作者：
Kavanagh, Kevin
影响因子：
9.8
作者：
Hamel, FG;Upward, JL;Duckworth, WC
通讯作者：
Duckworth, WC
影响因子：
2.8
作者：
Downes, Damien J.;Dayis, Meryl A.;Todd, Richard B.
通讯作者：
Todd, Richard B.
影响因子：
3.1
作者：
Hissen, AHT;Wan, ANC;Moore, MM
通讯作者：
Moore, MM