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bioRxiv · 10.1101/2025.09.09.675165

Systematic Mapping of Protein Interactions Underlying IL-2 Secretion in Human T Cells

Shin, S.·Rocamora, F.·Lewis, N. E.
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Abstract

Protein secretion plays a crucial role in maintaining immune homeostasis, yet the molecular interactions governing this process remain incompletely understood. While transcriptional and post-transcriptional regulation of protein expression is well characterized, the subcellular interactions between secreted proteins and trafficking machinery are less explored. To address this, we systematically mapped protein-protein interactions (PPIs) involved in the secretion of interleukin-2 (IL-2) from human T cells using proximity-based labeling coupled with mass spectrometry. Our analysis revealed significant enrichment of proteins associated with conventional secretory pathways, including ER-to-Golgi transport, protein folding, and vesicle-mediated trafficking. Functional validation confirmed that several of these proteins are critical for IL-2 secretion, underscoring their direct roles in cytokine processing. In addition, time-resolved profiling of PPIs and transcriptomic changes following T cell stimulation revealed dynamic remodeling of the cytokine secretion machinery, reflecting multilayered regulation at both the protein and gene expression levels. These findings offer a systems-level understanding of IL-2 secretion and identify new molecular components that can be targeted to modulate immune responses. This work provides a framework for dissecting complex secretory processes and has broad implications for therapeutic strategies in immune-related diseases.

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Shin, S., Rocamora, F., Lewis, N. E.. 2025-09-15. Systematic Mapping of Protein Interactions Underlying IL-2 Secretion in Human T Cells. https://doi.org/10.1101/2025.09.09.675165

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