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Loss of BRUCE reduces cellular energy level and induces autophagy by driving activation of the AMPK-ULK1 autophagic initiating axis
- Source :
- PLoS ONE, PLoS ONE, Vol 14, Iss 5, p e0216553 (2019)
- Publication Year :
- 2019
- Publisher :
- Public Library of Science, 2019.
-
Abstract
- Autophagy is an intracellular catabolic system. It delivers cellular components to lysosomes for degradation and supplies nutrients that promote cell survival under stress conditions. Although much is known regarding starvation-induced autophagy, the regulation of autophagy by cellular energy level is less clear. BRUCE is an ubiquitin conjugase and ligase with multi-functionality. It has been reported that depletion of BRUCE inhibits starvation-induced autophagy by blockage of the fusion step. Herein we report a new function for BRUCE in the dual regulation of autophagy and cellular energy. Depletion of BRUCE alone (without starvation) in human osteosarcoma U2OS cells elevated autophagic activity as indicted by the increased LC3B-II protein and its autophagic puncta as well as further increase of both by chloroquine treatment. Such elevation results from enhanced induction of autophagy since the numbers of both autophagosomes and autolysosomes were increased, and recruitment of ATG16L onto the initiating membrane structure phagophores was increased. This concept is further supported by elevated lysosomal enzyme activities. In contrast to starvation-induced autophagy, BRUCE depletion did not block fusion of autophagosomes with lysosomes as indicated by increased lysosomal cleavage of the GFP-LC3 fusion protein. Mechanistically, BRUCE depletion lowered the cellular energy level as indicated by both a higher ratio of AMP/ATP and the subsequent activation of the cellular energy sensor AMPK (pThr-172). The lower energy status co-occurred with AMPK-specific phosphorylation and activation of the autophagy initiating kinase ULK1 (pSer-555). Interestingly, the higher autophagic activity by BRUCE depletion is coupled with enhanced cisplatin resistance in human ovarian cancer PEO4 cells. Taken together, BRUCE depletion promotes induction of autophagy by lowering cellular energy and activating the AMPK-ULK1-autophagy axis, which could contribute to ovarian cancer chemo-resistance. This study establishes a BRUCE-AMPK-ULK1 axis in the regulation of energy metabolism and autophagy, as well as provides insights into cancer chemo-resistance.
- Subjects :
- 0301 basic medicine
Apoptosis
AMP-Activated Protein Kinases
Biochemistry
Inhibitor of Apoptosis Proteins
Cell Fusion
0302 clinical medicine
Ubiquitin
Medicine and Health Sciences
Tumor Cells, Cultured
Autophagy-Related Protein-1 Homolog
Electron Microscopy
Small interfering RNAs
Phosphorylation
Ovarian Neoplasms
Microscopy
Osteosarcoma
Multidisciplinary
biology
Cell Death
Chemistry
Kinase
Intracellular Signaling Peptides and Proteins
Cell biology
Ovarian Cancer
Nucleic acids
Gene Expression Regulation, Neoplastic
Oncology
Cell Processes
030220 oncology & carcinogenesis
Medicine
Female
Signal transduction
Cellular Structures and Organelles
Intracellular
Research Article
Signal Transduction
Cell Physiology
Cell Survival
Science
Autophagic Cell Death
Bone Neoplasms
Research and Analysis Methods
03 medical and health sciences
Genetics
Autophagy
Humans
Non-coding RNA
Autophagosomes
AMPK
Biology and Life Sciences
Cancers and Neoplasms
Cell Biology
DNA
ULK1
Gene regulation
030104 developmental biology
biology.protein
DNA damage
RNA
Transmission Electron Microscopy
Gene expression
Lysosomes
Energy Metabolism
human activities
Gynecological Tumors
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 14
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....23b9f2997197f86b0ce342ad871d41eb