Heat Shock Factor mediates actin phosphorylation in tissue integrity and age

热休克因子介导组织完整性和年龄的肌动蛋白磷酸化

• 批准号: 10565858
• 负责人: Peter Mahan Douglas
• 金额: $ 33.21万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565858
• 关键词: Actins; Adult; Age; Aging; Animals; Apical; Architecture; Base Sequence; Binding; Binding Sites; Biochemical; Biological Assay; Caenorhabditis elegans; Cells; Complex; Data; Defect; Deterioration; Digestion; Dyes; Elasticity; Epithelium; Escherichia coli; Exclusion; Functional disorder; Genes; Genetic; Genetic Epistasis; Goals; HSF1; Heat shock factor; Impairment; In Vitro; Intercellular Junctions; Internet; Intestines; Invaded; Laboratories; Link; Longevity; Maintenance; Mediating; Methods; Microfilaments; Mitogen-Activated Protein Kinases; Molecular; Motor; Myosin ATPase; Nematoda; Organ; Permeability; Phosphorylation; Phosphotransferases; Photobleaching; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Proteins; RNA Interference; Recovery; Regulation; Relaxation; Research; Role; Serine; Stress; Structure; Surface; System; Tensile Strength; Testing; Time; Tissues; Troponin; Troponin I; Untranslated Regions; Variant; age related; body system; cellular microvillus; experimental study; ferrofluid; functional disability; gene repression; heat shock transcription factor; in vivo; inorganic phosphate; intestinal barrier; intestinal epithelium; jun Oncogene; mimetics; physical property; reconstitution; resilience; vesicle transport

Project Summary/Abstract Aging involves the gradual decay of tissues, organs and organ systems. Early in this process, impermeability or selective permeability of tissues deteriorates and gives rise to increasing organ dysfunction. This phenomenon has been termed barrier dysfunction, yet the molecular mechanisms, which drive tissue “leakiness” and contribute to organ aging are unclear. To interrogate the underlying mechanism, we examine the aging intestine of the nematode, C. elegans, to determine how resiliency of the intestinal barrier withstands the test of time. Preliminary screens from my lab have linked age regulation by the Heat Shock transcription Factor, HSF-1, with the activity of the intestine-specific actin protein, ACT-5. Although expressed in a small number of cells and comprising less than 2% of total worm actin, ACT-5 plays an essential role in intestinal and organismal aging. Through the proposed five-year research period, we aim to understand how age-related decline in HSF-1 activity contributes to tissue dysfunction and animal aging. In particular, we will characterize the molecular mechanism of age progression in which HSF-1 dysregulation impairs cellular architecture and intestinal physiology. We speculate that age-associated decline in HSF-1 activity impairs specialized actin networks in intestinal epithelium, which ultimately compromise vesicular traffic, cell-cell junctional integrity and tissue barrier maintenance. We have already identified the stress-activated JUN kinase, KGB-1, as a repressed transcriptional target of HSF-1, which catalyzes phosphate addition to the ACT-5 protein within its binding site for the actin filament stabilizing Troponin complex. Accumulation of phosphorylated ACT-5 at serine residue 232 dramatically influences the structural integrity of the apical terminal web and vesicular transport across it. Overall, the proposed research will uncover a phosphorylation-dependent actin relaxation mechanism under HSF-1 control, which facilitates vesicular transport across dense, actin-rich “roadblocks” while still maintaining their structural rigidity and cellular architecture.

项目概要/摘要 衰老涉及组织、器官和器官系统的逐渐腐烂，在这个过程的早期，不渗透性或不渗透性。 组织的选择性渗透性恶化并导致器官功能障碍增加。 被称为屏障功能障碍，但驱动组织“渗漏”和 导致器官衰老的因素尚不清楚。为了探究其潜在机制，我们检查了衰老的肠道。 线虫，秀丽隐杆线虫，以确定肠道屏障的弹性如何经受住时间的考验。 我的实验室的初步筛选将热休克转录因子 HSF-1 的年龄调节与 肠道特异性肌动蛋白 ACT-5 的活性，尽管在少数细胞中表达。 ACT-5 占蠕虫肌动蛋白总量的不到 2%，在肠道和生物衰老中发挥着重要作用。 通过拟议的五年研究期，我们的目标是了解 HSF-1 活性与年龄相关的下降是如何发生的 特别是，我们将描述其分子机制。 HSF-1 失调会损害细胞结构和肠道生理学的年龄进展。 推测 HSF-1 活性与年龄相关的下降会损害肠道中的专门肌动蛋白网络 上皮，最终损害囊泡交通、细胞间连接完整性和组织屏障 我们已经鉴定出应激激活的 JUN 激酶 KGB-1 是一种抑制性转录因子。 HSF-1 的靶标，催化磷酸盐添加到 ACT-5 蛋白的肌动蛋白结合位点上 丝氨酸残基 232 处的磷酸化 ACT-5 显着积累。 影响顶端末端网络的结构完整性和穿过它的囊泡运输。 拟议的研究将揭示 HSF-1 控制下的磷酸化依赖性肌动蛋白松弛机制， 它促进囊泡运输穿过密集的、富含肌动蛋白的“路障”，同时仍然保持其结构 刚性和蜂窝结构。

项目成果

Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.

热休克因子减少沿肠道神经元轴的骨形态发生蛋白信号传导可延长寿命。

• 发表时间: 2022-09
• 影响因子: 7.8
• 作者: Arneaud, Sonja L B;McClendon, Jacob;Tatge, Lexus;Watterson, Abigail;Zuurbier, Kielen R;Madhu, Bhoomi;Gumienny, Tina L;Douglas, Peter M
• 通讯作者: Douglas, Peter M

Intracellular lipid surveillance: Modulating protein dynamics through lipid sensing.

细胞内脂质监测：通过脂质传感调节蛋白​​质动力学。

• 发表时间: 2022-12
• 作者: Watterson, Abigail;Douglas, Peter M
• 通讯作者: Douglas, Peter M