NUPR1 is a critical repressor of ferroptosis
Open Access
- 28 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-13
- https://doi.org/10.1038/s41467-021-20904-2
Abstract
Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.This publication has 79 references indexed in Scilit:
- Deciphering the Binding between Nupr1 and MSL1 and Their DNA-Repairing ActivityPLOS ONE, 2013
- Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell DeathClinical Cancer Research, 2012
- Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosisJCI Insight, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- Progressive Endoplasmic Reticulum Stress Contributes to Hepatocarcinogenesis in Fatty Acyl-CoA Oxidase 1–Deficient MiceThe American Journal of Pathology, 2011
- Endogenous HMGB1 regulates autophagyThe Journal of cell biology, 2010
- Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4IUBMB Life, 2009
- p8/nupr1 regulates DNA‐repair activity after double‐strand gamma irradiation‐induced DNA damageJournal of Cellular Physiology, 2009
- Direct multiplexed measurement of gene expression with color-coded probe pairsNature Biotechnology, 2008
- Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating ironNature, 2004