Cilia are microtubule-based organelles projecting from the cell surface with important sensory and motility functions.Ciliary defects are associated with diverse diseases collectively known as ciliopathies.However,the...Cilia are microtubule-based organelles projecting from the cell surface with important sensory and motility functions.Ciliary defects are associated with diverse diseases collectively known as ciliopathies.However,the molecular mechanisms that govern ciliogenesis remain not fully understood.Here,we demonstrate that ubiquitin-specific protease 21(USP21)is indispensable for cilium formation through its deubiquitinating activity.Usp21 knockout mice exhibit ciliary defects in multiple organs,such as the kidney,liver,and trachea.Our data also reveal a constant localization of USP21 at the centrosome and basal body during ciliogenesis.Mechanistically,USP21 interacts with dihydropyrimidinase-like 2(DPYSL2)at the centrosome and removes lysine 48-linked ubiquitination from DPYSL2.Loss of USP21 leads to the proteasomal degradation of DPYSL2 and causes a significant reduction in its centrosome abundance,ultimately resulting in ciliary defects.These findings thus identify a critical role for the USP21–DPYSL2 axis in ciliogenesis and have important implications for health and disease.展开更多
基金supported by the National Natural Science Foundation of China(32300694,32270807,32170829,and 31900538)the Shandong Natural Science Foundation(2022HWYQ-075)the Taishan Scholar Foundation of Shandong Province(tsqn202211109).
文摘Cilia are microtubule-based organelles projecting from the cell surface with important sensory and motility functions.Ciliary defects are associated with diverse diseases collectively known as ciliopathies.However,the molecular mechanisms that govern ciliogenesis remain not fully understood.Here,we demonstrate that ubiquitin-specific protease 21(USP21)is indispensable for cilium formation through its deubiquitinating activity.Usp21 knockout mice exhibit ciliary defects in multiple organs,such as the kidney,liver,and trachea.Our data also reveal a constant localization of USP21 at the centrosome and basal body during ciliogenesis.Mechanistically,USP21 interacts with dihydropyrimidinase-like 2(DPYSL2)at the centrosome and removes lysine 48-linked ubiquitination from DPYSL2.Loss of USP21 leads to the proteasomal degradation of DPYSL2 and causes a significant reduction in its centrosome abundance,ultimately resulting in ciliary defects.These findings thus identify a critical role for the USP21–DPYSL2 axis in ciliogenesis and have important implications for health and disease.
文摘目的通过对血管痴呆(vascular dementia,VD)模型大鼠行为学、免疫组化及蛋白质组学研究,探讨VD病理生理机制,揭示其背后隐含的关键神经生物分子。方法双侧颈总动脉结扎(2-VO法)建立VD大鼠模型,随机分为假手术组、VD模型组,Morris水迷宫评价大鼠的空间学习记忆能力;免疫组化方法检测海马脑区tau蛋白、p-tau蛋白、Aβ淀粉样蛋白表达量的改变;蛋白质组学技术分析鉴定VD模型中差异表达蛋白改变。结果(1)Mories水迷宫实验证实术后1、2、3、4、5 d VD组大鼠逃避潜伏期明显延长(82.7±22.3、82.2±25.1、71.5±31.7、68.3±9.2、60.2±18.9),与假手术组相比差异明显,有统计学意义(P<0.01,P<0.05);(2)VD组大鼠海马脑区Tau蛋白、P-Tau蛋白、Aβ淀粉样蛋白表达量显著上升(3.75±0.94、5.16±1.02、3.65±1.21),与假手术组相比差异显著,有统计学意义(P<0.05);(3)与假手术组相比,VD模型组共筛选发现21个差异蛋白点,质谱最终鉴定出4种蛋白表达上调,分别是α-烯醇化酶、硫氧还原蛋白、丝裂原活化蛋白激酶激酶1、二氢嘧啶酶相关蛋白;1种蛋白表达下调,即谷胱甘肽合成酶。结论 2-VO法成功制备了VD大鼠模型;蛋白质组学技术发现VD发病过程中关键蛋白。对详细阐述VD发病机制及VD治疗中可能的蛋白靶点提供理论依据和思路线索。
