Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autophagy is an important protein degradation pathway and a part of the innate immune system that is activated in the brain tissue during animal and human prion diseases. However, the possible mechanism by which prion infection triggers autophagy and the significance of activated autophagy on prion accumulation remain unknown. Here, we demonstrated that autophagic flux was enhanced in the persistent prion-infected cell line, SMB-S15. Knockdown of ATG5 and the presence of three autophagic inhibitors resulted in a significant increase of PrP(Sc). The mammalian target of rapamycin (MTOR) levels in SMB-S15 cells were also markedly decreased, in direct relation to PrP(Sc) accumulation. F-box and WD repeat domain containing 7 (FBXW7) levels in SMB-S15 cells and in the brains of scrapie-agent 263K-infected hamsters were upregulated at the early stage of infection, leading to active ubiquitination and degradation of MTOR. Knockdown of FBXW7 in SMB-S15 cells remarkably inhibited autophagic flux and increased PrP(Sc) accumulation. Thus, we conclude that prion infection induced the expression of FBXW7, which mediated MTOR ubiquitination and degradation, further altering phosphorylation status through cross talk between MTORC1 and AMPK and increasing autophagic flux. Autophagy may serve as innate immunity to degrade PrP(Sc) and maintain prion homeostasis.
...
PMID:FBXW7-Induced MTOR Degradation Forces Autophagy to Counteract Persistent Prion Infection. 2557 81

AMPK is a serine/threonine protein kinase that acts as a positive regulator of autophagy, by phosphorylating ULK1 at specific sites. A previous study demonstrated activation of the macroautophagic system in scrapie-infected experimental rodents and in certain human prion diseases, in which the essential negative regulator mTOR is severely inhibited. In this study, AMPK and ULK1 in the brains of hamsters infected with scrapie strain 263 K and in the scrapie-infected cell line SMB-S15 were analysed. The results showed an up-regulated trend of AMPK and AMPK-Thr172, ULK1 and ULK1-Ser555. Increases in brain AMPK and ULK1 occurred at an early stage of agent 263 K infection. The level of phosphorylated ULK1-Ser757 decreased during mid-infection and was only negligibly present at the terminal stage, a pattern that suggested a close relationship of the phosphorylated protein with altered endogenous mTOR. In addition, the level of LKB1 associated with AMPK activation was selectively increased at the early and middle stages of infection. Knockdown of endogenous ULK1 in SMB-S15 cells inhibited LC3 lipidation. These results showed that, in addition to the abolishment of the mTOR regulatory pathway, activation of the AMPK-ULK1 pathway during prion infection contributes to autophagy activation in prion-infected brain tissues.
 ...
PMID:Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection. 2642 66