NFE2L1-mediated proteasome function protects from ferroptosis

Abstract

ObjectiveFerroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood.Methods and ResultsHere we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis.ConclusionOur data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.Graphical abstractHighlightsProteasome function is diminished during ferroptosisNFE2L1-mediated proteasomal activity protects from ferroptosisThe ubiquitination of the GPX4-glutathione pathway is implicated in Nfe2l1 deficiencyNFE2L1 deficiency in brown fat is associated with hallmarks of ferroptosis

Recent progress in ferroptosis: inducers and inhibitors

“…For example, it has been recently reported that the proteasome is affected by inducers in ferroptosis, which is mediated by the transcription factor nuclear factor erythroid-2, like-1 (NFE2L1). The ferroptosis inducers RSL3 and FIN56 increase the activity of NFE2L1, but erastin does not have this effect [27]. Moreover, inhibiting the function of GPX4 directly will not cause the wavelike transmission of death between cell populations, while inhibition of other key targets reportedly showed transmission [6].…”

“…Reduce iron level Ferritin Prominin2 [90] ALOX15 miR-522 [95] miR-129-5p RP11-89 [94] Reduce lipid peroxides ACC1 LKB1-AMPK axis [97] / iNOS [98] Effects on the GSH/GPX4 axis System Xc − DKK1, OTUB1 [102,105] Regulate the proteasomal activity / NFE2L1 [27] role in many disease models [85]. In ɑ-tocopherol (Vitamin E) and analogs of Fer-1, such as SRS15-72B, SRS15-72A, SRS16-80 and SRS16-86, have similar functions albeit different effects and stabilities [7,85,86].…”

“…Ferroptosis inducers promote proteasomal activity and improve cell tolerance. Although the mechanism by which proteasomal activity protects cells from ferroptosis is still unclear, some evidence has been presented, suggesting that it may be related to ubiquitination [27].…”

Development and validation of a novel ferroptosis‑related lncRNA prognostic signature for pancreatic adenocarcinoma

“…However, p53 can also inhibit ferroptosis by the inhibition of dipeptidyl peptidase 4 or through the enhancement of cyclin dependent kinase inhibitor 1 A (61). It has been reported that proteasome function is often inhibited during ferroptosis (62). Numerous metabolic and degradation pathways, including the ubiquitin-proteasome system, orchestrate the complex ferroptotic response through the regulation of iron accumulation or lipid peroxidation (63).…”

Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis

“…Thus, oxidative stress is sensed and mitigated by GPX4 and its inactivation leads to lipid peroxidation and cell death in cells and mouse models (8). Interestingly, ferroptosis is linked to adaptive changes in protein homeostasis, as ferroptosis initiation is associated with diminished proteasomal activity and restoration of proteasomal activity protects cells from ferroptotic cell death (9). The ubiquitin-proteasome system (UPS) manages the degradation of unwanted, obsolete, or damaged proteins (10).…”