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.

项目总结/摘要 衰老包括组织、器官和器官系统的逐渐衰退。在这个过程的早期，不渗透性或 组织的选择性渗透性恶化并引起器官功能障碍的增加。这种现象 已被称为屏障功能障碍，但分子机制，驱动组织“泄漏”， 导致器官衰老的原因尚不清楚。为了探究潜在的机制，我们检查了老化的肠道， 线虫C. elegans，以确定肠道屏障的弹性如何经受时间的考验。 我实验室的初步筛选将热休克转录因子HSF-1的年龄调节与 的活性的丝氨酸特异性肌动蛋白，ACT-5。虽然在少数细胞中表达， ACT-5占蠕虫肌动蛋白总量的不到2%，在肠道和生物体衰老中起重要作用。 通过拟议的五年研究期，我们的目标是了解与年龄相关的HSF-1活性下降是如何发生的。 导致组织功能障碍和动物衰老。特别是，我们将描述分子机制 HSF-1失调损害细胞结构和肠道生理学的年龄进展。我们 推测与年龄相关的HSF-1活性下降损害了肠上皮细胞中特化的肌动蛋白网络， 上皮，最终损害囊泡运输、细胞-细胞连接完整性和组织屏障 上维护我们已经鉴定出应激激活的JUN激酶KGB-1是一种受抑制的转录因子， HSF-1的靶点，催化ACT-5蛋白与肌动蛋白结合位点内的磷酸盐加成 肌钙蛋白复合物丝稳定。磷酸化ACT-5在丝氨酸残基232处的积累显著增加了ACT-5的活性。 影响顶端末端网的结构完整性和囊泡穿过它的运输。总的来说， 提出的研究将揭示HSF-1控制下的磷酸化依赖性肌动蛋白松弛机制， 这有助于囊泡运输穿过密集的、富含肌动蛋白的“路障”，同时仍然保持它们的结构 刚性和细胞结构。

项目成果

Intracellular lipid surveillance: Modulating protein dynamics through lipid sensing.

• DOI: 10.1002/ctm2.1147
• 发表时间: 2022-12
• 期刊: Clinical and translational medicine
• 影响因子: 10.6

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

• DOI: 10.1111/acel.13693
• 发表时间: 2022-09
• 期刊: AGING CELL
• 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.