Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1

Tyrkalska, Sylwia D.; Pérez-Oliva, Ana B.; Rodríguez‐Ruiz, Lola; Martínez-Morcillo, Francisco J.; Alcaraz-Pérez, Francisca; Martínez-Navarro, Francisco J.; Lachaud, Christophe; Ahmed, Nouraiz; Schroeder, Timm; Pardo-Sánchez, Irene; Candel, Sergio; López-Muñoz, Azucena; Choudhuri, Avik; Rossmann, Marlies P.; Zon, Leonard I.; Cayuela, María L.; García‐Moreno, Diana; Mulero, Victoriano

doi:10.1016/j.immuni.2019.05.005

Cited by 63 publications

(83 citation statements)

References 85 publications

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“…In addition, the same study showed that the cleavage of GATA1 by caspase 1 was required for the final steps of hemin‐induced erythroid differentiation in K562 cells, thus pointing at an additional mechanism whereby the inflammasome could regulate erythropoiesis through GATA1. Importantly, just like for caspase 3, GATA1 was indeed shown to be a substrate for cleavage by caspase 1 in vitro …”

Section: Caspase‐mediated Gata1 Protein Cleavage and Terminal Erythromentioning

confidence: 88%

“…A recent study uncovered an additional caspase‐mediated mechanism for regulating GATA1 protein levels in hematopoiesis . Inflammasome activation in HSCs due to infection, led to caspase 1 activation and GATA1 cleavage and degradation, thus biasing cell fate decisions toward the myeloid lineage.…”

Section: Caspase‐mediated Gata1 Protein Cleavage and Terminal Erythromentioning

confidence: 99%

“…A recent study uncovered an additional caspasemediated mechanism for regulating GATA1 protein levels in hematopoiesis. 111 Inflammasome activation in HSCs due to infection, led to caspase 1 activation and GATA1 cleavage and degradation, thus biasing cell fate decisions toward the myeloid lineage. Inhibition of caspase 1 in murine HSCs resulted in the upregulation of GATA1 protein and an increase in megakaryocytic-erythroid (MegE) colony output at the expense of granulocytemonocyte (GM) colonies, suggesting an evolutionarily conserved mechanism for the inflammasome-regulating hematopoietic cell fate decisions by fine-tuning GATA1.…”

Section: Caspase-mediated Gata1 Protein Cleavage and Terminal Erythmentioning

confidence: 99%

“…Importantly, just like for caspase 3, GATA1 was indeed shown to be a substrate for cleavage by caspase 1 in vitro. 111 The role of the proteasome in erythropoiesis has been highlighted through the years, and it is well known that proteasome-inhibitor drugs used as anti-tumoral agents, especially in multiple myeloma, may cause anemia as an adverse event. [112][113][114] However, perhaps counterintuitively, chemical inhibition of the proteasome in murine erythroid progenitors, or loss of the proteasome shuttle protein Rad23b, results in reduced levels of GATA1 leading to early apoptosis in vitro and to anemia in vivo, respectively.…”

Section: Caspase-mediated Gata1 Protein Cleavage and Terminal Erythmentioning

confidence: 99%

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Regulation of GATA1 levels in erythropoiesis

et al. 2019

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GATA1 is considered as the "master" transcription factor in erythropoiesis. It regulates at the transcriptional level all aspects of erythroid maturation and function, as revealed by gene knockout studies in mice and by genome-wide occupancies in erythroid cells. The GATA1 protein contains two zinc finger domains and an N-terminal transactivation domain. GATA1 translation results in the production of the full-length protein and of a shorter variant (GATA1s) lacking the N-terminal transactivation domain, which is functionally deficient in supporting erythropoiesis. GATA1 protein abundance is highly regulated in erythroid cells at different levels, including transcription, mRNA translation, posttranslational modifications, and protein degradation, in a differentiationstage-specific manner. Maintaining high GATA1 protein levels is essential in the early stages of erythroid maturation, whereas downregulating GATA1 protein levels is a necessary step in terminal erythroid differentiation. The importance of maintaining proper GATA1 protein homeostasis in erythropoiesis is demonstrated by the fact that both GATA1 loss and its overexpression result in lethal anemia. Importantly, alterations in any of those GATA1 regulatory checkpoints have been recognized as an important cause of hematological disorders such as dyserythropoiesis (with or without thrombocytopenia), β-thalassemia, Diamond-Blackfan anemia, myelodysplasia, or leukemia. In this review, we provide an overview of the multilevel regulation of GATA1 protein homeostasis in erythropoiesis and of its deregulation in hematological disease. K E Y W O R D S

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Section: Caspase‐mediated Gata1 Protein Cleavage and Terminal Erythromentioning

confidence: 88%

Section: Caspase‐mediated Gata1 Protein Cleavage and Terminal Erythromentioning

confidence: 99%

Section: Caspase-mediated Gata1 Protein Cleavage and Terminal Erythmentioning

confidence: 99%

Section: Caspase-mediated Gata1 Protein Cleavage and Terminal Erythmentioning

confidence: 99%

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Regulation of GATA1 levels in erythropoiesis

et al. 2019

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“…In order to ensure that this production of IL-18 was dependent on caspase-1, M1 MDMs were treated with VX-765, a caspase-1 specific inhibitor [25–27], prior to either infection with HSV-1 or treatment with nigericin and LPS. IL-18 levels in cell supernatants were reduced to levels not significantly different than background in the presence of VX-765, suggesting that this IL-18 production is due to canonical caspase-1 activation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Karaba

Figueroa

Massaccesi

et al. 2019

Preprint

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20 Review and Editing 21 22 23 Abstract:24 The pro-inflammatory cytokines interleukin (IL)-1 and IL-18 are products of activation of the 25 inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex 26 type 1 (HSV-1). The release of IL-18 and IL-1 from monocytes/macrophages is critical for 27 protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and 28 how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, 29 we utilized both primary human monocyte derived macrophages and human monocytic cell 30 lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 31 activates inflammasome signaling in pro-inflammatory primary human macrophages.32 Additionally, HSV-1 inflammasome activation is dependent on nucleotide-binding domain and 33 leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule 34 containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 35 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). Ultraviolet irradiation of HSV-1 36 enhanced inflammasome activation, demonstrating that viral replication suppresses 37 inflammasome activation. These results confirm that HSV-1 is capable of activating the 38 inflammasome in human macrophages through an NLRP3 dependent process and that the virus 39 has an NLRP3 specific mechanism to inhibit inflammasome activation in monocytes and 40 macrophages. 41 42 43 44 3 45 Author Summary: 46The inflammasome is a multi-protein complex that forms in response to pathogens and 47 cellular damage. Active inflammasomes recruit pro-caspase-1 via ASC and cleave the cytokine 48 precursors pro-IL-1 and pro-IL-18 into mature IL-1 and IL-18. These cytokines serve to 49 activate other immune cells that either repair the damage or attempt to clear the invading 50 pathogen. Upon activation, the inflammasome also promotes an inflammatory form of cell 51 death called pyroptosis. Herpes simplex virus type 1 (HSV-1) is a common human pathogen that 52 can cause cold sores, genital ulcers, encephalitis, and blindness. HSV-1 infection leads to 53 induction of IL-1 and IL-18, but whether it is capable of activating inflammasomes in 54 macrophages, which play a role in severe forms of HSV-1 infection, was unclear. Here, we 55 infected both primary human macrophages and a macrophage/monocytic cell line, THP-1 cells, 56 with HSV-1. We found that HSV-1 does activate inflammasome signaling in macrophages in a 57 process dependent on NLRP3, ASC, and caspase-1. This is important because it illustrates the 58 mechanism by which HSV-1 infection leads to inflammasome activation in macrophages, known 59 to be crucial for protection from severe disease in mouse models. 60 61 62 63 64 65 66 4 67 Introduction: 68 The ability to quickly recognize and respond to pathogens is essential to host survival. 69 The first opportunity to do so lies in the innate immune response. One of the most essential 70 aspe...

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Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts

Adamiak

Abdel‐Latif

Bujko

et al. 2020

Stem Cell Rev and Rep

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Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and dangerassociated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.

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Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1

Cited by 63 publications

References 85 publications

Regulation of GATA1 levels in erythropoiesis

Regulation of GATA1 levels in erythropoiesis

Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts

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