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Publications of the Week

Hsp83 Loss Suppresses Proteasomal Activity Resulting in an Upregulation of Caspase-Dependent Compensatory Autophagy

By September 1, 2017No Comments

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 This week we profile a recent publication in Autophagy from Courtney Choutka (fourth from left, front row, below),
Nancy Erro Go (far left, below), and Dr. Sharon Gorski (pictured) at Simon Fraser University.

Can you provide a brief overview of your lab’s current research focus?

Our research lab focuses on the cellular process known as autophagy, or “self-eating”. Autophagy is an intracellular degradation and recycling process that promotes stress adaptation and cell survival. Our research program explores the contributions of autophagy to proteostasis, normal development, and cancer progression with a focus on breast and pancreatic cancers. We are also investigating the therapeutic potential of autophagy modulation in these cancers.

What is the significance of the findings in this publication?

In this publication we utilized the fruitfly model organism, Drosophila melanogaster, to discover novel relationships between two proteins that connect pathways important for protein homeostasis (proteostasis): autophagy, the ubiquitin proteasome system (UPS), and apoptosis. We found that the heat-shock protein Hsp83 normally suppresses autophagy by maintaining low levels of the effector caspase Dcp-1 with the support of the ubiquitin-proteasome system. Reduction in Hsp83 or UPS function led to an increase in the activation of compensatory autophagy that was dependent on Dcp-1, while the cell death observed in Hsp83 loss-of-function mutants was independent of Dcp-1. Our publication offers new insights into communication between these key proteostasis pathways and reveals unique targets and approaches to modulating these distinct cellular processes.

What are the next steps for this research?

The next step for this research is to investigate the evolutionary conservation of this newly discovered regulatory relationship in human cells. Currently we are performing human tissue culture experiments to evaluate if effector caspases in humans play a role in the activation of autophagy, similar to what we observed in Drosophila. Our findings could prove to be important for disease models because the human orthologue of Hsp83 (HSP90) is currently being tested as an anti-cancer target. Drugs targeting HSP90 might show further benefit when used in combination with certain caspase inhibitors which could still allow cell death but mitigate the cell survival process of autophagy.

This research is funded by:

We gratefully acknowledge funding from CIHR and NSERC.

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