Dissecting the Keap1/Nrf2 pathway through proteomics

Mass spectrometry-based proteomic technologies continue to illuminate the mechanism(s) and physiological importance of the KEAP1/NRF2 antioxidant signaling pathway. Proteomic analysis of the KEAP1 and NRF2 protein complex has revealed associated proteins and post-translational modifications, which together support new modes of regulation and therapeutic intervention opportunities for prevention and treatment. Emerging proteomic data depict a highly inter-connected signaling network containing numerous co-complexed proteins and post-translational modifications, the majority of which are of unknown functional significance. In this review, we have compiled the literature and public domain to produce protein interaction networks for KEAP1 and NRF2. Selected interacting proteins and their possible functional implications are covered. We also curated available proteomic datasets to create a comprehensive map of various post-translational modifications on KEAP1 and NRF2. Together, this evaluation illustrates the power of mass spectrometry-based protein sequencing to understand the signaling components and dynamics of the KEAP1–NRF2 pathway. Current challenges and future directions for mass spectrometry in antioxidant signaling are discussed.