Chemical proteomics reveals post-translational remodeling of endosomal pathways during macrophage activation.

Zhang, T. L.; Sanford, H.; Gabbasova, R. R.; van Vlimmeren, A. E.; Kalaidzidis, Y.; Kojima, H.; Wayne, C. R.; Biswas, J.; Banerjee, P.; Zhang, B.; Abdel-Wahab, O.; Zerial, M.; Vinogradova, E. V.

doi:10.64898/2026.09.25.754469

bioRxiv · 10.64898/2026.09.25.754469

Chemical proteomics reveals post-translational remodeling of endosomal pathways during macrophage activation.

Zhang, T. L.·Sanford, H.·Gabbasova, R. R.·van Vlimmeren, A. E.·Kalaidzidis, Y.·Kojima, H.·Wayne, C. R.·Biswas, J.·Banerjee, P.·Zhang, B.·Abdel-Wahab, O.·Zerial, M.·Vinogradova, E. V.

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Abstract

Macrophages are central regulators of innate immunity, yet the post-translational mechanisms that enable rapid inflammatory responses remain incompletely understood. Here, we integrated transcriptomics, unenriched proteomics, phosphoproteomics, metabolomics, and cysteine reactivity profiling to comprehensively characterize primary human macrophages following Toll-like receptor and Stimulator of Interferon Genes (STING) activation. This approach revealed substantial discordance between transcript- and protein-level changes, as well as extensive post-translational remodeling. Differentially reactive cysteines were enriched in proteins involved in small-GTPase signaling, vesicular trafficking, and the endo-lysosomal system. Reactivity changes in two subunits of the endosomal mRNA-transport FERRY complex nominated it as a candidate target of inflammation-associated post-translational regulation. Biochemical and imaging analyses established FERRY complex assembly and early endosomal localization in primary human macrophages and identified DISC1 as a previously unrecognized FERRY-associated protein. This work provides a comprehensive resource of biochemical and post-translational remodeling during macrophage activation and implicates endosome-associated mRNA transport in innate immune regulation.

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Zhang, T. L., Sanford, H., Gabbasova, R. R., van Vlimmeren, A. E., Kalaidzidis, Y., Kojima, H., Wayne, C. R., Biswas, J., Banerjee, P., Zhang, B., Abdel-Wahab, O., Zerial, M., Vinogradova, E. V.. 2026-10-01. Chemical proteomics reveals post-translational remodeling of endosomal pathways during macrophage activation.. https://doi.org/10.64898/2026.09.25.754469

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