Protein aggregation as a cellular response to oxidative stress induced by heme and iron.
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.
Laboratório de Imunoreceptores e Sinalização, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Luiz R C
LR
Vasconcellos
Laboratório de Inflamação e Imunidade, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Fabianno F
FF
Dutra
Laboratório de Imunoreceptores e Sinalização, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Mariana S
MS
Siqueira
Laboratório de Alvos Moleculares, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Heitor A
HA
Paula-Neto
Laboratório de Inflamação e Imunidade, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Jennifer
J
Dahan
Laboratório de Imunoreceptores e Sinalização, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Ellen
E
Kiarely
Laboratório de Inflamação e Imunidade, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Leticia A M
LA
Carneiro
Laboratório de Inflamação e Imunidade, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil.
Marcelo T
MT
Bozza
Laboratório de Imunoreceptores e Sinalização, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21.941-902, Brazil; leo.travassos@biof.ufrj.br.
Leonardo H
LH
Travassos
D000818:Animals; D005293:Ferritins / Q000378:metabolism; D057809:HEK293 Cells; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D066329:Protein Aggregates; D059748:Proteolysis; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D006418:Heme; D005293:Ferritins; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
ALIS; autophagy; heme; iron; p62/SQSTM1