Global Thiol Proteome Analysis: A Novel Insights into the Macrophage Inflammatory Response and Its Regulation

Global Thiol Proteome Analysis Provides Novel Insights into the Macrophage Inflammatory Response and Its Regulation by the Thioredoxin System

News Release, Redox Medicine 2023 , France – March 20, 2023

Oxidative modifications of cysteine (Cys) thiols regulate various physiological processes, including inflammatory responses. The thioredoxin (Trx) system plays a key role in thiol redox control. The aim of this study was to characterize the dynamic cysteine proteome of human macrophages upon activation by the prototypical proinflammatory agent, bacterial lipopolysaccharide (LPS), and/or perturbation of the Trx system.

Dr. Benhar and his team profiled the cellular and redox proteome of human THP-1-derived macrophages during the early phase of LPS activation and/or inhibition of Trx system activity by auranofin (AF) by employing a peptide-centric, resin-assisted capture, redox proteomic workflow. Among 4200 identified cysteines, oxidation of nearly 10% was selectively affected by LPS or AF treatments.

Notably, the proteomic analysis uncovered a subset of ∼100 thiols, mapped to proteins involved in diverse processes, whose oxidation is antagonistically regulated by LPS and Trx. Compared with the redox proteome, the cellular proteome was largely unchanged, highlighting the importance of redox modification as a mechanism that allows for rapid modulation of macrophage activities in response to a proinflammatory or pro-oxidant insult.

Structural–functional analyses provided mechanistic insights into redox regulation of selected proteins, including the glutathione-synthesizing enzyme, glutamate–cysteine ligase, and the autophagy adaptor, SQSTM1/p62, suggesting mechanisms by which macrophages adapt and fine-tune their responses according to a changing inflammatory and redox environment.

This study provides a rich resource for further characterization of redox mechanisms that regulate macrophage inflammatory activities. The dynamic thiol redox proteome allows macrophages to efficiently respond and adapt to redox and inflammatory challenges. 

Article DOI.

Dr. Benhar will be joining Redox Medicine 2023 to give a talk about the effects of reactive sulfur species in macrophage activation and regulation of apoptosis/necrosis pathways in cancer cells. You can submit a related abstract here.

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