TBC1D1(Tre-2/BUB2/cdc1 domain family 1)和TBC1D4(又名Akt Substrate of 160 k Da,AS160)均为骨骼肌细胞内的GTP酶激活蛋白(Rab-GTPase activating proteins,Rab-GAP),参与骨骼肌细胞葡萄糖转运蛋白4(GLUT4)在细胞内的转位过程,调节...TBC1D1(Tre-2/BUB2/cdc1 domain family 1)和TBC1D4(又名Akt Substrate of 160 k Da,AS160)均为骨骼肌细胞内的GTP酶激活蛋白(Rab-GTPase activating proteins,Rab-GAP),参与骨骼肌细胞葡萄糖转运蛋白4(GLUT4)在细胞内的转位过程,调节骨骼肌细胞葡萄糖转运。最新研究表明,TBC1D1和TBC1D4在有氧运动促进骨骼肌细胞葡萄糖转运过程中发挥重要作用,骨骼肌细胞胰岛素信号通路活性下降引起GLUT4转位异常、导致骨骼肌细胞葡萄糖转运能力下降。有氧运动能够显著改善机体能量代谢水平,已被广泛应用于临床肥胖、胰岛素抵抗、2型糖尿病等代谢性疾病的治疗。本文综述TBC1D1和TBC1D4在有氧运动促进骨骼肌细胞葡萄糖转运中的作用,以期为运动防治代谢性疾病的机制研究提供理论依据。展开更多
Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse form...Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse formation and function.The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.However,their functions in regulating the formation of NMJ are less understood.Here,we report that TBC1D5 is required for inhibition of synaptic growth,and loss of TBC1D5 leads to abnormal presynaptic terminal development,including excessive satellite boutons and branch formation.Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5mutant boutons.Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5.Unexpectedly,we find that TBC1D5 is functionally linked to Rab6,in addition to Rab7,to regulate synaptic growth.Mechanistically,we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type Ⅱ receptor Wishful Thinking(Wit)at NMJ.Overall,our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity,which negatively regulates BMP signaling through inhibiting Wit level.展开更多
文摘TBC1D1(Tre-2/BUB2/cdc1 domain family 1)和TBC1D4(又名Akt Substrate of 160 k Da,AS160)均为骨骼肌细胞内的GTP酶激活蛋白(Rab-GTPase activating proteins,Rab-GAP),参与骨骼肌细胞葡萄糖转运蛋白4(GLUT4)在细胞内的转位过程,调节骨骼肌细胞葡萄糖转运。最新研究表明,TBC1D1和TBC1D4在有氧运动促进骨骼肌细胞葡萄糖转运过程中发挥重要作用,骨骼肌细胞胰岛素信号通路活性下降引起GLUT4转位异常、导致骨骼肌细胞葡萄糖转运能力下降。有氧运动能够显著改善机体能量代谢水平,已被广泛应用于临床肥胖、胰岛素抵抗、2型糖尿病等代谢性疾病的治疗。本文综述TBC1D1和TBC1D4在有氧运动促进骨骼肌细胞葡萄糖转运中的作用,以期为运动防治代谢性疾病的机制研究提供理论依据。
基金supported by research grants from the National Natural Science Foundation of China(31671510 and 31871461 to H.H.31771592 to W.X.)。
文摘Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse formation and function.The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.However,their functions in regulating the formation of NMJ are less understood.Here,we report that TBC1D5 is required for inhibition of synaptic growth,and loss of TBC1D5 leads to abnormal presynaptic terminal development,including excessive satellite boutons and branch formation.Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5mutant boutons.Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5.Unexpectedly,we find that TBC1D5 is functionally linked to Rab6,in addition to Rab7,to regulate synaptic growth.Mechanistically,we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type Ⅱ receptor Wishful Thinking(Wit)at NMJ.Overall,our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity,which negatively regulates BMP signaling through inhibiting Wit level.
