Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions

Jordan Currie, Vyshnavi Manda, Sean K. Robinson, Celine Lai, Vertica Agnihotri, Veronica Hidalgo, R. W. Ludwig, Kai Zhang, Jay Pavelka, Zhao V. Wang, June-Wha Rhee, Maggie P. Y. Lam and Edward Lau ()
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Jordan Currie: University of Colorado School of Medicine
Vyshnavi Manda: University of Colorado School of Medicine
Sean K. Robinson: University of Colorado School of Medicine
Celine Lai: Stanford University
Vertica Agnihotri: City of Hope Comprehensive Cancer Center
Veronica Hidalgo: University of Colorado School of Medicine
R. W. Ludwig: University of Colorado School of Medicine
Kai Zhang: Beckman Research Institute, City of Hope National Medical Center
Jay Pavelka: University of Colorado School of Medicine
Zhao V. Wang: Beckman Research Institute, City of Hope National Medical Center
June-Wha Rhee: City of Hope Comprehensive Cancer Center
Maggie P. Y. Lam: University of Colorado School of Medicine
Edward Lau: University of Colorado School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The spatial and temporal distributions of proteins are critical to protein function, but cannot be directly assessed by measuring protein bundance. Here we describe a mass spectrometry-based proteomics strategy, Simultaneous Proteome Localization and Turnover (SPLAT), to measure concurrently protein turnover rates and subcellular localization in the same experiment. Applying the method, we find that unfolded protein response (UPR) has different effects on protein turnover dependent on their subcellular location in human AC16 cells, with proteome-wide slowdown but acceleration among stress response proteins in the ER and Golgi. In parallel, UPR triggers broad differential localization of proteins including RNA-binding proteins and amino acid transporters. Moreover, we observe newly synthesized proteins including EGFR that show a differential localization under stress than the existing protein pools, reminiscent of protein trafficking disruptions. We next applied SPLAT to an induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) model of cancer drug cardiotoxicity upon treatment with the proteasome inhibitor carfilzomib. Paradoxically, carfilzomib has little effect on global average protein half-life, but may instead selectively disrupt sarcomere protein homeostasis. This study provides a view into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.

Date: 2024
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DOI: 10.1038/s41467-024-46600-5

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