Document text
Principal Investigator: Joseph Genereux
Organization: UNIVERSITY OF CALIFORNIA RIVERSIDE
Fiscal Year: 2024
Award: $310,125
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
The secretory pathway must fold and traffic one third of the proteome, while handling an
exceptional dynamic range of client load. Quality control mechanisms prevent proteostasis in the
secretory pathway from being overwhelmed by proteins in non-native states. One such
mechanism is preemptive quality control (preQC), wherein ER stress inhibits ER translocation of
nascent proteins. This process protects the ER from being overwhelmed with nascent protein
during misfolded protein stress, a situation associated with diverse disease included diabetes and
neurodegenerative diseases. However, this protection leads to secretory protein accumulating in
the cytosol, which can be proteotoxic and lead to cell death and dysfunction. Due to
methodological limitations, the substrates, causes, mechanism, and consequences of preQC are
largely unknown. Hence, the physiological relevance of preQC, while expected to be significant,
is not well understood. We propose to apply our recently developed assay for secretory protein
mistargeting to systematically characterize preQC. We will identify which stresses induce preQC
for a series of protein substrates in secretory cells from diverse human lineages. We will identify
what factors govern triaging of mistargeted secretory proteins between aggregation and
degradation mechanisms. Because our assay is performed in living cells, we will determine which
signaling pathways mediate induction of preQC by ER stress. Finally, we will extend our assay to
allow proteome-wide quantification of both basal and stress-dependent ER mistargeting. This
extension will allow us to identify the factors that govern susceptibility of proteins to preQC. The
outcome of the proposed research will be systematic characterization of how the cell remodels
ER translocation in response to stress.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATF6><ATF6 gene><ATP-Dependent Proteolysis Factor 1><Activating Transcription Factor 6><Affinity><Assay><Bioassay><Biochemical><Biological Assay><Biology><Cell Body><Cell Culture Techniques><Cell Death><Cells><Cessation of life><Chemicals><Client><Coupled><Cytosol><Death><Degenerative Neurologic Disorders><Development><Diabetes Mellitus><Disease><Disorder><Dysfunction><ER stress><Endoplasmic Reticulum><Ergastoplasm><Experimental Designs><Foundations><Functional disorder><HMG-20><Health><Heat shock proteins><High Mobility Protein 20><Human><Impairment><Individual><Intervention><Intervention Strategies><Investigation><Investigators><Label><Location><Macropain><Macroxyproteinase><Maintenance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methodology><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Multicatalytic Proteinase><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Outcome><Pathway interactions><Physiologic><Physiological><Physiopathology><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Predisposition><Process><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Modification><Protein translocation><Proteins><Proteome><Proteomics><Proteosome><Quality Control><Reporting><Research><Research Personnel><Researchers><Role><Route><Secretory Cell><Series><Signal Pathway><Stress><Surface Proteins><Susceptibility><System><Transmembrane Protein Transport><Triage><Ubiquitin><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><biological adaptation to stress><cell culture><cell cultures><cell type><conformation><conformational><conformational state><conformationally><conformations><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diabetes><endoplasmic reticulum stress><experience><interventional strategy><misfolded protein><misfolded proteins><multicatalytic endopeptidase complex><necrocytosis><neurodegenerative illness><new technology><non-Native><nonnative><novel><novel technologies><pathophysiology><pathway><prevent><preventing><protein homeostasis><proteostasis><proteotoxic><proteotoxic protein><proteotoxicity><proteotoxin><reaction; crisis><response><secretory protein><sensor><social role><stress protein><stress response><stress; reaction><stressor>