Targeted protein degradation(TPD)technology mainly utilizes the natural degradation systems within cells to specific and efficient degradation of disease-related proteins1.The ubiquitin-proteasome system(UPS)is the mo...Targeted protein degradation(TPD)technology mainly utilizes the natural degradation systems within cells to specific and efficient degradation of disease-related proteins1.The ubiquitin-proteasome system(UPS)is the most important way of protein degradation in eukaryotic cells,which is involved in more than 80%of degradation processes2.Molecular glues are mostly small molecules to stabilize existing interactions between two proteins or induce new protein-protein interactions3.In the case of molecular glues between the target protein and an E3 ligase.展开更多
Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network.Identification of novel regulators of cellular senescence and elucidation of their molecular mec...Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network.Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discoveryof new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPaseprotein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditiselegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulatedsenescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence.Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreasesp53 stability by attenuating the interaction between p14ARF and MDM2;on the other hand, hCINAP promotes MDM2 transcriptionvia inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively,our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlyingthe aging process.展开更多
文摘Targeted protein degradation(TPD)technology mainly utilizes the natural degradation systems within cells to specific and efficient degradation of disease-related proteins1.The ubiquitin-proteasome system(UPS)is the most important way of protein degradation in eukaryotic cells,which is involved in more than 80%of degradation processes2.Molecular glues are mostly small molecules to stabilize existing interactions between two proteins or induce new protein-protein interactions3.In the case of molecular glues between the target protein and an E3 ligase.
基金supported by the National Natural Science Foundation of China(82130081,32270756,and 81730080)the National Key Research and Development Program of China(2022YFA1302803)the Natural Science Foundation of Beijing Municipality(5212008).
文摘Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network.Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discoveryof new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPaseprotein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditiselegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulatedsenescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence.Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreasesp53 stability by attenuating the interaction between p14ARF and MDM2;on the other hand, hCINAP promotes MDM2 transcriptionvia inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively,our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlyingthe aging process.
