A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy.
Eukaryotes have two major intracellular protein degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Inhibition of proteasomal activities has been previously shown to induce autophagy, indicating a coordinated and complementary relationship between these two systems. However, little is known about the regulation of the UPS by autophagy. In this study, we showed for the first time that proteasomes were activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy-related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. The induction was evidenced by the increased proteasomal activities and the upregulation of proteasomal subunits, including the proteasome β5 subunit, PSMB5. Co-inhibition of the proteasome and autophagy also synergistically increased the accumulation of polyubiquitinated proteins. Collectively, our findings suggest that proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition. Our studies unveiled a novel regulatory mechanism between the two protein degradation pathways.
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Xiao J
XJ
Wang
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Jun
J
Yu
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Sunny H
SH
Wong
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Alfred S L
AS
Cheng
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Francis K L
FK
Chan
Department of Surgery; Faculty of Medicine; Chinese University of Hong Kong; Hong Kong.
Simon S M
SS
Ng
School of Biomedical Sciences; Chinese University of Hong Kong; Hong Kong.
Chi H
CH
Cho
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
Joseph J Y
JJ
Sung
Institute of Digestive Disease and State Key Laboratory of Digestive Disease; Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics; Chinese University of Hong Kong; Hong Kong.
William K K
WK
Wu
D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
SQSTM1; autophagy; chloroquine; proteasome; protein degradation