自噬
生物
双分子荧光互补
死孢子体1
细胞生物学
袋3
帕金
自噬相关蛋白13
分子生物学
生物化学
细胞凋亡
蛋白激酶A
帕金森病
基因
激酶
病理
疾病
蛋白质磷酸化
医学
作者
Ji Hyun Shin,Soo‐Young Park,Doo Sin Jo,Na Yeon Park,Joon Bum Kim,Ji-Eun Bae,Yoon Kyung Jo,Jung Jin Hwang,Jina Lee,Dong-Gyu Jo,Jin Cheon Kim,Yong Keun Jung,Jae‐Young Koh,Dong‐Hyung Cho
出处
期刊:Autophagy
[Informa]
日期:2019-03-19
卷期号:15 (9): 1495-1505
被引量:26
标识
DOI:10.1080/15548627.2019.1586249
摘要
Several studies have shown that dysfunction of macroautophagy/autophagy is associated with many human diseases, including neurodegenerative disease and cancer. To explore the molecular mechanisms of autophagy, we performed a cell-based functional screening with SH-SY5Y cells stably expressing GFP-LC3, using an siRNA library and identified TMED10 (transmembrane p24 trafficking protein 10), previously known as the γ-secretase-modulating protein, as a novel regulator of autophagy. Further investigations revealed that depletion of TMED10 induced the activation of autophagy. Interestingly, protein-protein interaction assays showed that TMED10 directly binds to ATG4B (autophagy related gene 4B cysteine peptidase), and the interaction is diminished under autophagy activation conditions such as rapamycin treatment and serum deprivation. In addition, inhibition of TMED10 significantly enhanced the proteolytic activity of ATG4B for LC3 cleavage. Importantly, the expression of TMED10 in AD (Alzheimer disease) patients was considerably decreased, and downregulation of TMED10 increased amyloid-β (Aβ) production. Treatment with Aβ increased ATG4B proteolytic activity as well as dissociation of TMED10 and ATG4B. Taken together, our results suggest that the AD-associated protein TMED10 negatively regulates autophagy by inhibiting ATG4B activity.Abbreviations: Aβ: amyloid-β; AD: Alzheimer disease; ATG: autophagy related; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CD: cytosolic domain; GFP: green fluorescent protein; GLUC: Gaussia luciferase; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LD: luminal domain; PD: Parkinson disease; ROS: reactive oxygen species; siRNA: small interfering RNA; SNP: single-nucleotide polymorphisms; TD: transmembrane domain; TMED10: transmembrane p24 trafficking protein 10; VC: C terminus of Venus fluorescent protein; VN: N terminus of Venus fluorescent protein.
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