Much effort has been taken to identify genetic or transcriptomic changes that might underlie drug action, cellular responses and drug resistance. Protein degradation, which represents a terminal step of regulation on protein homeostasis (proteostasis) and function, constitutes an essential but often under-explored part of cellular responses to intrinsic or extrinsic stimuli, such as stress or drug treatment. Dysregulated protein degradation, a critical aspect of proteostasis deficiency, is known to associate with a variety of devastating human diseases including cancer and neurodegenerative diseases.
Profiling global protein turnover is thus essential for elucidating the molecular basis of health or disease biology, and drug action and resistance, and for the development of therapeutic intervention into cancer and other diseases. However, monitoring global protein turnover remains challenging, mainly due to technical restraints.
Dr. HU Ronggui’s group in the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) developed and applied a dual-fluorescence-based Protein Turnover Assay (ProTA) to quantitatively profile global changes in human protein degradome upon BTZ-induced proteasomal inhibition.
ProTA and subsequent network analyses delineate potential molecular basis for BTZ action and tumor drug resistance in BTZ chemotherapy. Finally, combined use of BTZ with drugs targeting the ProTA-identified key genes or pathways in BTZ action reduced BTZ resistance in multiple myeloma cells.
Remarkably, BTZ stabilizes proteasome subunit PSMC1 and proteasome assembly factor PSMD10, suggesting a previously under-appreciated mechanism for regulating proteasome homeostasis. Therefore, ProTA is a novel tool for profiling human protein degradome to elucidate potential mechanisms of drug action and resistance, which might facilitate therapeutic development targeting proteostasis to treat human disorders.
Recently, this work was published in the latest issue of Cell Research. under the title “Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis”. Under the supervision by Dr. HU Ronggui, the study was led by first author: Ph.D candidates YU Tao from Dr. HU Ronggui’s group in SIBCB. The major collaborators included Drs. WANG Hongyan, RUAN Kangcheng from SIBCB, Dr ZHANG Yan from INS as well as Drs CHEN Zi, ZHANG Tao from Fudan University.
This work was supported by the National Natural Science Foundation of China, the award from CAS to RH and the Ministry of Science and Technology, China. Prof. HUwas also supported by a Sanofi-aventis SIBS Young Investigator award and funding from the Cancer Center of Xuhui Central Hospital, Shanghai Institute of Neurosciences and the Instrument Developing Project ofCAS.
Figure. A schematic view of the work flow for ProTA (Protein turnover assay)
(Image provided by Prof. HU Ronggui`s group)
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