ArticleProceedings of the National Academy of Sciences of the United States of America2016
Protein aggregation as a cellular response to oxidative stress induced by heme and iron.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 90 citations in OpenAlex.
- DcR3 Suppresses Lipopolysaccharide-Induced Aggresome-like Structures in Macrophages via Inhibition of Reactive Oxygen Species and p38 MAPK.International journal of molecular sciences · 2026Article
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- Dietary iron attenuates epigenetic aging through DNA methylation remodeling and extends survival in older adults.Clinical epigenetics · 2025Article
- Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.Cellular and molecular neurobiology · 2025Article
- ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.JCI insight · 2025Article
- The Underestimated Role of Iron in Frontotemporal Dementia: A Narrative Review.International journal of molecular sciences · 2024Review
- The Neural Palette of Heme: Altered Heme Homeostasis Underlies Defective Neurotransmission, Increased Oxidative Stress, and Disease Pathogenesis.Antioxidants (Basel, Switzerland) · 2024Review
- The relation between BTK expression and iron accumulation of myeloid cells in multiple sclerosis.Brain pathology (Zurich, Switzerland) · 2024Article
- Role Transformation of HSPA8 to Heme-peroxidase After Binding Hemin to Catalyze Heme Polymerization.The protein journal · 2024Article
- Diet-Modifiable Redox Alterations in Ageing and Cancer.Sub-cellular biochemistry · 2024Review
- Review
- Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression.Multiple sclerosis and related disorders · 2023Article
- Itraconazole Confers Cytoprotection Against Neurodegenerative Disease-Associated Abnormal Protein Aggregation.Molecular neurobiology · 2023Article
- Depletion assisted hemin affinity (DAsHA) proteomics reveals an expanded landscape of heme-binding proteins in the human proteome.Metallomics : integrated biometal science · 2023Article
- Amyloid-like RIP1/RIP3 RHIM Fragments' Characterization and Application as a Drug Depot.Molecules (Basel, Switzerland) · 2023Article
- HMOX1 Promotes Ferroptosis in Mammary Epithelial Cells via FTH1 and Is Involved in the Development of Clinical Mastitis in Dairy Cows.Antioxidants (Basel, Switzerland) · 2022Article
- The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures.BMC biology · 2022Article
- Heme as an inducer of cerebral damage in hemorrhagic stroke: potential therapeutic implications.Neural regeneration research · 2022Article
- Siah2-GRP78 interaction regulates ROS and provides a proliferative advantage to Helicobacter pylori-infected gastric epithelial cancer cells.Cellular and molecular life sciences : CMLS · 2022Article
- Modeling oxidative injury response in human kidney organoids.Stem cell research & therapy · 2022Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hemolytic diseases include a variety of conditions with diverse etiologies in which red blood cells are destroyed and large amounts of hemeproteins are released. Heme has been described as a potent proinflammatory molecule that is able to induce multiple innate immune responses, such as those triggered by TLR4 and the NLRP3 inflammasome, as well as necroptosis in macrophages. The mechanisms by which eukaryotic cells respond to the toxic effects induced by heme to maintain homeostasis are not fully understood, however. Here we describe a previously uncharacterized cellular response induced by heme: the formation of p62/SQTM1 aggregates containing ubiquitinated proteins in structures known as aggresome-like induced structures (ALIS). This action is part of a response driven by the transcription factor NRF2 to the excessive generation of reactive oxygen species induced by heme that results in the expression of genes involved in antioxidant responses, including p62/SQTM1. Furthermore, we show that heme degradation by HO-1 is required for ALIS formation, and that the free iron released on heme degradation is necessary and sufficient to induce ALIS. Moreover, ferritin, a key protein in iron metabolism, prevents excessive ALIS formation. Finally, in vivo, hemolysis promotes an increase in ALIS formation in target tissues. Our data unravel a poorly understood aspect of the cellular responses induced by heme that can be explored to better understand the effects of free heme and free iron during hemolytic diseases such as sickle cell disease, dengue fever, malaria, and sepsis.
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