Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1–Nuclear factor erythroid 2-related factor 2 protein-protein interaction (PIN1–NRF2 PPI)

The PIN1–NRF2 protein-protein interaction is a pivotal regulatory mechanism in the cellular antioxidant defense system and a major contributor to therapeutic resistance in cancer [1, 2]. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a unique enzyme that recognizes phosphorylated serine or threonine residues followed by proline (pSer/Thr-Pro) and catalyzes their cis-trans isomerization, thereby inducing conformational changes in target proteins [1, 3]. In this specific interaction, PIN1 binds to the Nuclear factor erythroid 2-related factor 2 (NRF2), a master transcription factor that orchestrates the expression of numerous antioxidant and detoxifying genes [2, 4]. This isomerization stabilizes NRF2 by interfering with its recognition by E3 ubiquitin ligases, such as the Keap1-independent β-TrCP pathway, thus preventing its proteasomal degradation [4, 5]. High levels of both PIN1 and NRF2 are frequently observed in various cancers, where they cooperate to protect malignant cells from the oxidative stress induced by chemotherapy and radiation [2, 6]. Consequently, disrupting the PIN1–NRF2 axis using PIN1 inhibitors like all-trans retinoic acid (ATRA) or KPT-6566 has emerged as a promising strategy to overcome chemoresistance and enhance the efficacy of standard treatments [5, 6]. However, because PIN1 regulates a wide array of proteins involved in the cell cycle and apoptosis, therapeutic targeting must address potential safety concerns related to systemic toxicity and off-target effects [1, 3]. Sources: [1] UniProt (Q13526, Q16236); [2] Sun, X. et al. (2020) PubMed: 32433614; [3] Zhou, X. Z., & Lu, K. P. (2016) PubMed: 27338439; [4] Liang, J. et al. (2019) PubMed: 31163165; [5] Wei, Z. et al. (2015) PubMed: 26063003; [6] Urbano, A. G. et al. (2019) PubMed: 30861164.

Other names

PIN1-NRF2 complexPIN1-NFE2L2 interactionPeptidyl-prolyl isomerase 1–Nuclear factor erythroid 2-related factor 2 interactionPIN1-NRF2 axis

Inhibition of PIN1-mediated prolyl isomerization of NRF2, which prevents NRF2 stabilization and promotes its degradation via the proteasome, thereby increasing cellular sensitivity to oxidative stress and chemotherapy.