Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, United States.
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, United States; Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, United States; Center for Physics of Evolving Systems, University of Chicago, Chicago, IL, United States.
J Mol Biol. 2024 Jul 15;436(14):168642. doi: 10.1016/j.jmb.2024.168642. Epub 2024 Jun 5.
The heat shock response (HSR) is a gene regulatory program controlling expression of molecular chaperones implicated in aging, cancer, and neurodegenerative disease. Long presumed to be activated by toxic protein aggregates, recent work suggests a new functional paradigm for the HSR in yeast. Rather than toxic aggregates, adaptive biomolecular condensates comprised of orphan ribosomal proteins (oRP) and stress granule components have been shown to be physiological chaperone clients. By titrating away the chaperones Sis1 and Hsp70 from the transcription factor Hsf1, these condensates activate the HSR. Upon release from Hsp70, Hsf1 forms spatially distinct transcriptional condensates that drive high expression of HSR genes. In this manner, the negative feedback loop controlling HSR activity - in which Hsf1 induces Hsp70 expression and Hsp70 represses Hsf1 activity - is embedded in the biophysics of the system. By analogy to phosphorylation cascades that transmit information via the dynamic activity of kinases, we propose that the HSR is organized as a condensate cascade that transmits information via the localized activity of molecular chaperones.
热休克反应 (HSR) 是一种基因调控程序，控制着分子伴侣的表达，这些分子伴侣与衰老、癌症和神经退行性疾病有关。长期以来，人们一直认为它是由有毒的蛋白质聚集体激活的，但最近的研究工作表明，HSR 在酵母中存在一个新的功能范例。与其说是有毒的聚集体，由孤儿核糖体蛋白 (oRP) 和应激颗粒成分组成的适应性生物分子凝聚物被证明是生理伴侣的客户。通过从转录因子 Hsf1 中滴定掉伴侣蛋白 Sis1 和 Hsp70，这些凝聚物激活了 HSR。从 Hsp70 释放后，Hsf1 形成空间上不同的转录凝聚物，从而驱动 HSR 基因的高表达。通过这种方式，控制 HSR 活性的负反馈循环——其中 Hsf1 诱导 Hsp70 表达，而 Hsp70 抑制 Hsf1 活性——嵌入到系统的生物物理学中。通过类比于通过激酶的动态活性传递信息的磷酸化级联，我们提出 HSR 被组织为一个凝聚物级联，通过分子伴侣的局部活性传递信息。
