Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be achieved. Here we 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.     

Dynamic task-belief is an integral part of decision-making

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Testing predictions of foraging theory for a sit-and-wait forager, Anolis gingivinus

Research in foraging theory has been dominated by studies ofactive foragers choosing among patches and among prey withina patch. Studies of central-place foraging have mainly focusedon loading decisions of an animal provisioning a central place.The problem faced by a sit-and-wait forager that encountersprey at a distance has received little attention. In this studywe tested foraging theory predictions for such foragers, Anolisgingivinus females in the West Indies island of Anguilla. Wepresented lizards with antlion larvae at various distances.Experiment 1 showed that an individual's probability of pursuingprey decreases with the prey's distance and is best describedby a sigmoidal function (which may be as steep as a step function).This function's inflection point defines a cutoff distance.Experiment 3 tested how cutoff distance changes as a functionof prey size. Cutoff distances were greater for larger prey,as predicted for an energy-maximizing forager. Experiments 2and 4 tested how cutoff distance changes as a function of preyabundance. As predicted, cutoff distance were greater at a sitewhere prey abundance was lower. Furthermore, cutoff distancesdecreased immediately following prey augmentation and returnedto previous values within one day of ending augmentation. Thus,moles' foraging behavior is a dynamic process, consistent withthe qualitative predictions of foraging theory. We attributethe success of this study in supporting fundamental foragingtheory predictions to the lizards exhibiting natural behaviorunder field conditions and to particular advantages of studyingsit-and-wait foragers.