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HUAFEI DIAO received the B.E., M.E., and Ph.D. degrees from Space Engineering University. He is currently an Associate Professor with Space Engineering University. ...doi:10.1109/access.2020.2977451 fatcat:fwhnmtnmp5edzajlcvfedyenra
The Unc-51 like autophagy activating kinase 1 (ULK1) complex plays a central role in the initiation stage of autophagy. However, the function of ULK1 in the late stage of autophagy is unknown. Here, we report that ULK1, a central kinase of the ULK1 complex involved in autophagy initiation, promotes autophagosome-lysosome fusion. PKCα phosphorylates ULK1 and prevents autolysosome formation. PKCα phosphorylation of ULK1 does not change its kinase activity; however, it decreasesdoi:10.1038/s41467-018-05449-1 pmid:30154410 fatcat:fjk35nqxrvdujbw3jlmd3phuke
more »... ome fusion by reducing the affinity of ULK1 for syntaxin 17 (STX17). Unphosphorylated ULK1 recruited STX17 and increased STX17′s affinity towards synaptosomal-associated protein 29 (SNAP29). Additionally, phosphorylation of ULK1 enhances its interaction with heat shock cognate 70 kDa protein (HSC70) and increases its degradation through chaperone-mediated autophagy (CMA). Our study unearths a key mechanism underlying autolysosome formation, a process in which the kinase activity of PKCα plays an instrumental role, and reveals the significance of the mutual regulation of macroautophagy and CMA in maintaining the balance of autophagy. A utophagy is a process of metabolic degradation at the cellular level in which organelles or portions of the cytosol are sequestered by double-membrane autophagosomes and fused with lysosomes for degradation. Autophagy plays a crucial role in a variety of biochemical processes, including cell survival, oxidative stress, removal of redundant organelles and proteins, and resistance to infection by pathogens 1 . The ULK1/ATG13/FIP200 complex initiates the occurrence of autophagy in mammalian cells. ULK1 is a serine/threonine-specific protein kinase. The ULK1 complex is made of autophagyrelated protein 13 (ATG13), which contains the HORMA domain, the FIP200 (RB1CC1) scaffold, and autophagy-related protein 101 (ATG101) 2 . The ULK1 complex senses the nutrient status of cells to initiate or terminate autophagy. ULK1 can be phosphorylated by mammalian target of rapamycin complex 1 (mTORC1) or AMP-activated protein kinase (AMPK) to prevent or promote autophagy 3,4 . As a kinase, ULK1 also phosphorylates many autophagy-related targets, such as beclin1 (BECN1), vacuolar protein sorting 34 (VPS34), and ATG101, that are important for autophagy initiation 5 . Protein kinase C (PKC) is a family of serine/threonine protein kinases. PKCs are activated by increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca 2+ ) 6 . Fifteen members of the PKC family in humans are divided into three subfamilies based on their second messenger requirements: conventional (or classical), novel or atypical. PKC regulates autophagy by phosphorylating microtubule-associated protein 1 A/1B-light chain 3 (LC3), a marker of autophagy 7 . Autophagosome fusion into lysosomes degrades molecular components necessary for cell survival. Several SNARE (soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptors) proteins are involved in this step. They are STX17, vesicle-associated membrane protein 8 (VAMP8) and SNAP29 8 . Upon membrane fusion, the SNARE complex forms a parallel four-helix bundle consisting of the Qa-, Qb-, Qc-, and R-SNAREs. STX17 is a Qa-SNARE on autophagosomes that interacts with the Qb/Qc motif of SNAP29. This complex fuses with the R-SNARE named VAMP8, which is on lysosomal membranes, thus completing the fusion of autophagosomes and lysosomes. Autophagy-related 14 homolog (ATG14L) also plays a critical role in SNARE-mediated fusion 9 . It was previously reported that ATG14L also promotes autophagy in the initiating step via binding to the BECN1/VPS34/VPS15 complex 10 , which suggests that one factor can play multiple roles in different stages of autophagy. In the present study, we found that ULK1 mediates fusion of the autophagosome to the lysosome by interacting with STX17. This activity is dependent on its phosphorylation state via PKCα. When the nutrient signal activates PKCα, ULK1 is phosphorylated and degraded by chaperone-mediated autophagy (CMA).
500 Common Chinese Proverbs and Colloquial Expressions
Guónèi de rén wèn qh ta guówài zgnmeyàng shí, ta df diào ményá wfng dù lh yàn, shud "thng hfo de." ... B: Ànshud zhèxib lièzhì yàophn gbnbgn bù kgnéng tdngguò jifnyàn de, dànshì zhìyào gdngsc huafèi jùzc xínghuì, suiyh shgnpc bùmén, jifnyàn bùmén chùchù kailqdbng, zuìhòu yàophn jiù jìnrù shìchfng le. ...doi:10.4324/9781315884585-10 fatcat:z5i7hwfmufespfhnsagc75kqwm