Neuritin affects the activity of neuralized-like 1 by promoting degradation and weakening its affinity for substrate  

作　　者：Jingling Zhu Yu Li Chen Zhong Meiyi Zhu Yan Zheng Anying Xiong Pingping Meng Liya Shan Yang Li Jin Huang 

机构地区：[1]Department of Biochemistry and Molecular Biology,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]the Key Laboratory of Xinjiang Endemic&Ethnic Diseases and Department of Biochemistry,Shihezi University School of Medicine,Shihezi 832002,China [3]the First Affiliated Hospital of Shihezi University School of Medicine,Shihezi 832000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第10期1650-1658,共9页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(Nos.81771173 to J.H.and 32060164 to J.Z.).

摘　　要：Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation.Our previous research revealed the mechanism by which neuritin inhibits Notch signaling through interaction with neuralized-like 1(Neurl1)to promote neurite growth.However,how neuritin regulates Notch signaling through Neurl1 has not been elucidated.Here,we first confirm that neuritin is an upstream regulator of Neurl1 and inhibits Notch signaling through Neurl1.Neurl1 is an E3 ubiquitin ligase that can promote ubiquitination and endocytosis of the Notch1 ligand Jagged1.Therefore,we observe the effect of neuritin on the ligase activity of Neurl1.The results indicate that neuritin inhibits Neurl1 activity by reducing the ubiquitination level and endocytosis of the target protein Jagged1.Moreover,we find that decreased activity of Neurl1 results in reduced expression of Notch receptor Notch intracellular domain(NICD)and downstream target gene hairy and enhancer of split-1(HES1).Furthermore,we investigate how neuritin affects Neurl1 enzyme activity.The results show that neuritin not only weakens the affinity between Neurl1 and Jagged1 but also promotes the degradation of Neurl1 by the 26S proteasome pathway.Taken together,our results suggest that neuritin negatively regulates Notch signaling by inhibiting the activity of Neurl1,promoting the degradation of Neurl1 and weakening the affinity of Neurl1 for Jagged1.Our study clarifies the molecular mechanisms of neuritin in regulating the Notch signaling pathway and provides new clues about how neuritin mediates neural regeneration and plasticity.

关 键 词：NEURITIN neuralized-like 1 UBIQUITINATION DEGRADATION Notch signaling pathway 

分 类 号：Q78[生物学—分子生物学]