Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA, United States.
Department of Genome Sciences, University of Washington, Seattle, WA, United States.
Semin Cell Dev Biol. 2019 Apr;88:21-35. doi: 10.1016/j.semcdb.2018.05.015. Epub 2018 Jun 6.
Canalization, or phenotypic robustness in the face of environmental and genetic perturbation, is an emergent property of living systems. Although this phenomenon has long been recognized, its molecular underpinnings have remained enigmatic until recently. Here, we review the contributions of the molecular chaperone Hsp90, a protein that facilitates the folding of many key regulators of growth and development, to canalization of phenotype - and de-canalization in times of stress - drawing on studies in eukaryotes as diverse as baker's yeast, mouse ear cress, and blind Mexican cavefish. Hsp90 is a hub of hubs that interacts with many so-called 'client proteins,' which affect virtually every aspect of cell signaling and physiology. As Hsp90 facilitates client folding and stability, it can epistatically suppress or enable the expression of genetic variants in its clients and other proteins that acquire client status through mutation. Hsp90's vast interaction network explains the breadth of its phenotypic reach, including Hsp90-dependent de novo mutations and epigenetic effects on gene regulation. Intrinsic links between environmental stress and Hsp90 function thus endow living systems with phenotypic plasticity in fluctuating environments. As environmental perturbations alter Hsp90 function, they also alter Hsp90's interaction with its client proteins, thereby re-wiring networks that determine the genotype-to-phenotype map. Ensuing de-canalization of phenotype creates phenotypic diversity that is not simply stochastic, but often has an underlying genetic basis. Thus, extreme phenotypes can be selected, and assimilated so that they no longer require environmental stress to manifest. In addition to acting on standing genetic variation, Hsp90 perturbation has also been linked to increased frequency of de novo variation and several epigenetic phenomena, all with the potential to generate heritable phenotypic change. Here, we aim to clarify and discuss the multiple means by which Hsp90 can affect phenotype and possibly evolutionary change, and identify their underlying common feature: at its core, Hsp90 interacts epistatically through its chaperone function with many other genes and their gene products. Its influence on phenotypic diversification is thus not magic but rather a fundamental property of genetics.
canalization，或面对环境和遗传干扰时表型的稳健性，是生命系统的一种涌现特性。尽管这种现象早已被认识，但直到最近，其分子基础仍然是个谜。在这里，我们回顾了分子伴侣 Hsp90 的贡献，Hsp90 促进了许多生长和发育关键调节剂的折叠，它对表型的 canalization 和在压力下的 de-canalization 有影响——这是基于从真核生物（如面包酵母、鼠耳草和盲眼墨西哥洞穴鱼）中进行的研究。Hsp90 是一个与许多所谓的“客户蛋白”相互作用的中心，这些蛋白几乎影响到细胞信号转导和生理学的每一个方面。由于 Hsp90 促进客户蛋白的折叠和稳定性，它可以在遗传上抑制或使客户蛋白及其通过突变获得客户状态的其他蛋白的遗传变异表达。Hsp90 庞大的相互作用网络解释了其表型的广泛范围，包括 Hsp90 依赖性的新生突变和对基因调控的表观遗传效应。因此，环境压力与 Hsp90 功能之间的内在联系使生命系统在波动的环境中具有表型可塑性。随着环境干扰改变 Hsp90 的功能，它们也改变了 Hsp90 与其客户蛋白的相互作用，从而重新布线决定基因型到表型图的网络。随之而来的表型去 canalization 产生了不仅仅是随机的表型多样性，而且通常具有潜在的遗传基础。因此，极端表型可以被选择并同化，使得它们不再需要环境压力来表现。除了作用于现有遗传变异外，Hsp90 干扰还与新生变异的频率增加以及几种表观遗传现象有关，所有这些都有可能产生可遗传的表型变化。在这里，我们旨在澄清和讨论 Hsp90 影响表型和可能的进化变化的多种方式，并确定它们的共同特征：在其核心，Hsp90 通过其伴侣功能与许多其他基因及其基因产物相互作用。因此，它对表型多样化的影响不是魔术，而是遗传学的一个基本特性。
