Abstract：
:Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.
journal_name
Naturejournal_title
Natureauthors
Zou Y,Henry WS,Ricq EL,Graham ET,Phadnis VV,Maretich P,Paradkar S,Boehnke N,Deik AA,Reinhardt F,Eaton JK,Ferguson B,Wang W,Fairman J,Keys HR,Dančík V,Clish CB,Clemons PA,Hammond PT,Boyer LA,Weinberg RA,Schreiberdoi
10.1038/s41586-020-2732-8subject
Has Abstractpub_date
2020-09-01 00:00:00pages
603-608issue
7826eissn
0028-0836issn
1476-4687pii
10.1038/s41586-020-2732-8journal_volume
585pub_type
杂志文章相关文献
NATURE文献大全abstract：:Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent s...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature13608
更新日期：2014-09-04 00:00:00
abstract：:Simple mathematical models of the transmission dynamics of human immunodeficiency virus help to clarify some of the essential relations between epidemiological factors, such as distributed incubation periods and heterogeneity in sexual activity, and the overall pattern of the AIDS epidemic. They also help to identify ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/326137a0
更新日期：1987-03-12 00:00:00
abstract：:Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, an...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature25015
更新日期：2018-01-04 00:00:00
abstract：:RNA interference is an evolutionarily conserved surveillance mechanism that responds to double-stranded RNA by sequence-specific silencing of homologous genes. Here we show that transgene expression can be suppressed in adult mice by synthetic small interfering RNAs and by small-hairpin RNAs transcribed in vivo from D...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/418038a
更新日期：2002-07-04 00:00:00
abstract：:Early co-transcriptional events during eukaryotic ribosome assembly result in the formation of precursors of the small (40S) and large (60S) ribosomal subunits. A multitude of transient assembly factors regulate and chaperone the systematic folding of pre-ribosomal RNA subdomains. However, owing to a lack of structura...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature26156
更新日期：2018-04-05 00:00:00
abstract：:The transcription factor NF-kappaB is composed of homodimeric and heterodimeric complexes of Rel/NF-kappaB-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-kappaB/p50 and NF-kappaB2/p52 . The NF-kappaB1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-med...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/16946
更新日期：1999-01-28 00:00:00
abstract：:Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). Thes...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/344767a0
更新日期：1990-04-19 00:00:00
abstract：:Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also sup...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature06306
更新日期：2007-11-22 00:00:00
abstract：:Human T-cell leukaemias and lymphomas associated with the human T-cell leukaemia viruses (HTLV) are invariably neoplasms of cells with mature T-lymphocyte phenotype. Epstein-Barr virus-transformed B- lymphoycte lines which are productively infected with HTLV may be isolated from patients with HTLV malignancies, but no...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/309276a0
更新日期：1984-05-17 00:00:00
abstract：:The spread of antibiotic resistance in Gram-negative bacteria has sustained a continuing search for new agents with antibacterial activity against this important class of bacterial pathogen. Because the biosynthesis of lipopolysaccharide (LPS) is unique to Gram-negative bacteria and required by them for growth and vir...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/329162a0
更新日期：1987-09-10 00:00:00
abstract：:Wrists, ankles and digits distinguish tetrapod limbs from fins, but direct evidence on the origin of these features has been unavailable. Here we describe the pectoral appendage of a member of the sister group of tetrapods, Tiktaalik roseae, which is morphologically and functionally transitional between a fin and a li...
journal_title：Nature
pub_type： 历史文章,杂志文章
doi：10.1038/nature04637
更新日期：2006-04-06 00:00:00
abstract：:Saturn's largest moon, Titan, remains an enigma, explored only by remote sensing from Earth, and by the Voyager and Cassini spacecraft. The most puzzling aspects include the origin of the molecular nitrogen and methane in its atmosphere, and the mechanism(s) by which methane is maintained in the face of rapid destruct...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature04122
更新日期：2005-12-08 00:00:00
abstract：: ...
journal_title：Nature
pub_type： 评论,新闻
doi：10.1038/d41586-018-07240-0
更新日期：2018-11-01 00:00:00
abstract：:The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiolo...
journal_title：Nature
pub_type： 杂志文章,评审
doi：10.1038/nature10763
更新日期：2012-01-18 00:00:00
abstract：:Activated T lymphocytes differentiate into effector cells tailored to meet disparate challenges to host integrity. For example, type 1 and type 2 helper (T(H)1 and T(H)2) cells secrete cytokines that enhance cell-mediated and humoral immunity, respectively. The chemokine monocyte chemoattractant protein-1 (MCP-1) can ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35006097
更新日期：2000-03-23 00:00:00
abstract：:Transforming growth factor-alpha (TGF-alpha) is a mitogenically active polypeptide hormone produced by acutely proliferating neoplastic and embryonic tissues. Molecular cloning of TGF-alpha cDNA from human and rat has indicated that this factor is synthesized as part of a larger precursor, proTGF-alpha. An intriguing ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/326883a0
更新日期：1987-04-30 00:00:00
abstract：:DNA mismatch repair is critical for increasing replication fidelity in organisms ranging from bacteria to humans. MutS protein, a member of the ABC ATPase superfamily, recognizes mispaired and unpaired bases in duplex DNA and initiates mismatch repair. Mutations in human MutS genes cause a predisposition to hereditary...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35037509
更新日期：2000-10-12 00:00:00
abstract：:OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease1,2 and embryonic lethality during mouse development3. Here we show that OTULIN promo...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/s41586-018-0256-2
更新日期：2018-07-01 00:00:00
abstract：:The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35038090
更新日期：2000-10-19 00:00:00
abstract：:Spacecraft observations show that the presence of lightning activity is not confined to the terrestrial atmosphere, but is also found in the atmospheres of Venus, Jupiter and Saturn. Lightning activity may also occur in Titan's thick atmosphere. Calculations show that lightning produces a significant fraction of the...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/328509a0
更新日期：1987-08-06 00:00:00
abstract：:The human serum response factor is a transcription factor belonging to the MADS domain protein family with members characterized from the plant and animal kingdoms. The X-ray crystal structure of the serum response factor core in a specific-recognition DNA complex shows that the functions of DNA binding, dimerization ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/376490a0
更新日期：1995-08-10 00:00:00
abstract：:Regulation of messenger RNA translation is central to eukaryotic gene expression control. Regulatory inputs are specified by them RNA untranslated regions (UTRs) and often target translation initiation. Initiation involves binding of the 40S ribosomal small subunit (SSU) and associated eukaryotic initiation factors (e...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature18647
更新日期：2016-07-28 00:00:00
abstract：:In Drosophila melanogaster, the rRNA genes (rDNA) are clustered at single sites on two non-homologous chromosomes, the X and Y. Examination of the structure of X and Y rDNAs with restriction endonucleases reveals that the X rDNA contains repeating units not present in the Y. Such observations, as well as genetic evide...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/263027a0
更新日期：1976-09-02 00:00:00
abstract：: ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/d41586-019-00599-8
更新日期：2019-02-01 00:00:00
abstract：:Microcrystals of the lipoprotein-phosphoprotein complex which are found in the oocytes of Xenopus laevis were examined using electron microscopy. Analysis of Fourier transforms of the images of the (010) and (001) projections showed the space group to be P2(1)22(1). Ten projections were combined to produce a map of th...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/272028a0
更新日期：1978-03-02 00:00:00
abstract：:Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologu...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35002615
更新日期：2000-02-24 00:00:00
abstract：:Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes....
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature09542
更新日期：2010-12-16 00:00:00
abstract：:Originally described by Lugaresi et al. in 1986 (ref. 1), fatal familial insomnia (FFI) is a rare inherited neurological disease characterized by the subacute progression of intractable insomnia and other autonomic abnormalities, cerebellar and pyramidal signs, myoclonus and dementia; neuropathologically, the major fe...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/376434a0
更新日期：1995-08-03 00:00:00
abstract：:Mitogen-activated protein kinases, MAP kinases or ERKs (extracellular signal-regulated kinases) are rapidly stimulated by growth-promoting factors acting on a variety of cell-surface receptors. In turn, ERKs phosphorylate and regulate key intracellular enzymes and transcription factors involved in the control of cellu...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/369418a0
更新日期：1994-06-02 00:00:00
abstract：:Magma intrusions and eruptions commonly produce abrupt changes in seismicity far from magma conduits that cannot be associated with the diffusion of pore fluids or heat. Such 'swarm' seismicity also migrates with time, and often exhibits a 'dog-bone'-shaped distribution. The largest earthquakes in swarms produce after...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature00997
更新日期：2002-09-05 00:00:00
