Overexpression of p62/SQSTM1 promotes the degradations of abnormally accumulated PrP mutants in cytoplasm and relieves the associated cytotoxicities via autophagy-lysosome-dependent way.
The protein of p62/sequestosome 1 (SQSTM1), a key cargo adaptor protein involved in autophagy-lysosome degradation, exhibits inclusion bodies structure in cytoplasm and plays a protective role in some models of neurodegenerative diseases. Some PrP mutants, such as PrP-CYTO and PrP-PG14, also form cytosolic inclusion bodies and trigger neuronal apoptosis either in cultured cells or in transgenic mice. Here, we demonstrated that the cellular p62/SQSTM1 incorporated into the inclusion bodies formed by expressing the abnormal PrP mutants, PrP-CYTO and PrP-PG14, in human embryonic kidney 293 cells. Overexpression of p62/SQSTM1 efficiently relieved the cytosolic aggregations and cell apoptosis induced by the abnormal PrPs. Autophagy-lysosome inhibitors instead of proteasome inhibitor sufficiently blocked the p62/SQSTM1-mediated degradations of abnormal PrPs. Overexpression of p62/SQSTM1 did not alter the levels of light chain 3 (LC3) in the cells expressing various PrPs. However, more complexes of p62/SQSTM1 with LC3 were detected in the cells expressing the misfolded PrPs. These data imply that p62/SQSTM1 plays an important role in the homeostasis of abnormal PrPs via autophagy-lysosome-dependent way.
State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing, 102206, People's Republic of China.
Yin
Y
Xu
Jin
J
Zhang
Chan
C
Tian
Ke
K
Ren
Yu-E
YE
Yan
Ke
K
Wang
Hui
H
Wang
Cao
C
Chen
Jing
J
Wang
Qi
Q
Shi
Xiao-Ping
XP
Dong
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D000071456:Sequestosome-1 Protein
D048868:Adaptor Proteins, Signal Transducing; D011328:Prions; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein