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Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.

Madison T Wright¹, Bibek Timalsina¹, Valeria Garcia Lopez²

¹Department of Chemistry, Vanderbilt University, Nashville, TN, 37240, USA.

Molecular Systems Biology

|August 5, 2024

Summary

We developed time-resolved interactome profiling (TRIP) to study protein interactions in diseases. TRIP revealed altered protein dynamics in congenital hypothyroidism, identifying key targets for potential therapeutic intervention.

Keywords:

Bioorthogonal Protein Labeling Hypothyroidism Proteostasis Temporal Proteomics Thyroglobulin

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Area of Science:

Cellular Biology
Biochemistry
Molecular Medicine

Background:

Protein-protein interactions are crucial for cellular functions and disease pathogenesis.
Understanding the dynamics of these interactions is essential for comprehending cellular processes and disease states.
Aberrant protein interactions contribute to various pathological conditions, including protein misfolding diseases.

Purpose of the Study:

To develop a quantitative mass spectrometry method for mapping protein-protein interactions with time resolution at an organelle-wide scale.
To apply this method, termed time-resolved interactome profiling (TRIP), to investigate aberrant protein interaction dynamics in congenital hypothyroidism.
To identify novel therapeutic targets by elucidating the temporal coordination of protein homeostasis in disease.

Main Methods:

Development of time-resolved interactome profiling (TRIP), a quantitative mass spectrometry-based approach.
Application of TRIP to map de novo protein-protein interactions in the context of congenital hypothyroidism.
Functional siRNA screening to identify key protein degradation components involved in disease pathophysiology.

Main Results:

TRIP successfully mapped de novo protein-protein interactions with temporal resolution.
Altered temporal interactions of thyroglobulin with folding, redox, and glycosylation pathways were identified in congenital hypothyroidism.
VCP and TEX264 were identified as critical protein degradation factors, and their inhibition rescued mutant prohormone secretion.

Conclusions:

The study provides novel insights into the temporal coordination of protein homeostasis.
The TRIP method offers a powerful tool for investigating protein-folding diseases and other cellular processes.
Findings highlight VCP and TEX264 as potential therapeutic targets for congenital hypothyroidism.