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/文摘

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.