Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging structural and functional evidence

Nuclear factor erythroid 2-related factor 2 (NRF2), a redox-sensitive transcription factor, is a master regulator of cellular adaptation to diverse types of stressors. Under basal conditions, the regulation of NRF2 is governed by Kelch-like ECH-associated protein 1 (KEAP1), an adaptor subunit of the CUL3-based E3 ubiquitin ligase, which promotes the ubiquitination and subsequent degradation of NRF2. However, when electrophilic or oxidative stressors alter the conformation of the KEAP1–NRF2 complex, KEAP1 loses its regulatory control over newly synthesized NRF2, leading to its accumulation and nuclear translocation, where it exerts transcriptional activity. NRF2 stability and activity are also shaped by a broader spectrum of protein–protein interactions (PPIs), including recently emerging regulators such as peptidyl prolyl isomerase (PIN1). Significantly, many of these dynamic PPI networks are regulated by post-translational modifications (PTMs), which, in turn, can be governed by these PPIs. While major PTMs such as phosphorylation and ubiquitination constitute the central regulatory processes, atypical or less-characterized modifications, including SUMOylation and O-GlcNAcylation, are gaining increasing attention for their tissue and condition-specific roles. This review compiles the latest structural and functional evidence on well-known as well as understudied PTMs and PPIs of NRF2, emphasizing the dynamic interplay between these regulatory mechanisms in shaping NRF2 signaling under physiological and stress conditions. • Compartmentalized PTMs and partner crosstalk collectively orchestrate NRF2 activity. • Phosphorylation events modulate NRF2 binding to KEAP1, β-TrCP, PIN1, and others. • Noncanonical PTMs and condition-specific partners dynamically reshape NRF2 function. • The regulatory relevance and downstream impact of NRF2 S40 phosphorylation remain open. • Modulating NRF2 interaction networks offers selective therapeutic opportunities.