Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi
Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi
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DOI：
10.1371/journal.pgen.1007884
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发表时间：
2018-12
期刊：
影响因子：
4.5
通讯作者：
Valentina Del Olmo Toledo;R. Puccinelli;P. Fordyce;J. C. Pérez
中科院分区：
文献类型：
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作者：
Valentina Del Olmo Toledo;R. Puccinelli;P. Fordyce;J. C. Pérez
甾醇调节元件结合蛋白 (SREBP) 是碱性螺旋-环-螺旋转录调节因子，可控制高等真核生物和一些真菌中甾醇生物合成基因的表达。令人惊讶的是，SREBP 不调节子囊菌酵母（糖菌亚门）中的甾醇生物合成，因为该作用被传递给该进化枝中不相关的转录调节因子。尽管如此，SREBP 在子囊菌酵母菌念珠菌等真菌中扩增，引发了关于它们在这些生物体中的作用和进化的问题。在此，我们报道真菌 SREBP 的 DNA 结合偏好随着功能的扩展而多样化。我们确定真菌 SREBP 的几个分支优先结合非回文 DNA 序列，这与高等真核生物中大多数碱性螺旋-环-螺旋蛋白（包括 SREBP）识别的回文 DNA 基序相反。可能的祖先蛋白的重建和生化特征表明，该家族中内在的 DNA 结合混杂性是通过真菌 SREBP 不同分支中的替代机制解决的。此外，我们发现人类共生酵母白色念珠菌中的两个 SREBP 驱动转录级联，抑制厌氧条件下的形态转换。防止这种形态转变会增强白色念珠菌在哺乳动物肠道（真菌的天然生态位）的定殖。因此，我们的结果说明了 DNA 结合偏好的多样化如何促进真核转录调节因子家族的功能扩展。
The Sterol Regulatory Element Binding Proteins (SREBPs) are basic-helix-loop-helix transcription regulators that control the expression of sterol biosynthesis genes in higher eukaryotes and some fungi. Surprisingly, SREBPs do not regulate sterol biosynthesis in the ascomycete yeasts (Saccharomycotina) as this role was handed off to an unrelated transcription regulator in this clade. The SREBPs, nonetheless, expanded in fungi such as the ascomycete yeasts Candida spp., raising questions about their role and evolution in these organisms. Here we report that the fungal SREBPs diversified their DNA binding preferences concomitantly with an expansion in function. We establish that several branches of fungal SREBPs preferentially bind non-palindromic DNA sequences, in contrast to the palindromic DNA motifs recognized by most basic-helix-loop-helix proteins (including SREBPs) in higher eukaryotes. Reconstruction and biochemical characterization of the likely ancestor protein suggest that an intrinsic DNA binding promiscuity in the family was resolved by alternative mechanisms in different branches of fungal SREBPs. Furthermore, we show that two SREBPs in the human commensal yeast Candida albicans drive a transcriptional cascade that inhibits a morphological switch under anaerobic conditions. Preventing this morphological transition enhances C. albicans colonization of the mammalian intestine, the fungus’ natural niche. Thus, our results illustrate how diversification in DNA binding preferences enabled the functional expansion of a family of eukaryotic transcription regulators.