The levels of reactive oxygen species (ROS) are critical for various functions, including proliferation, differentiation, and apoptosis, that influence cell fate decisions. ROS levels are regulated by a specialized system that maintains the reduction and oxidation (redox) balance. Thioredoxin (TRX) plays an important role in cellular signaling through the TRX system (TRX, TRX reductase, and NADPH). This system reduces ROS levels and interacts with various cellular pathways [1,2]. Thioredoxin-interacting protein (TXNIP) is a negative regulator of TRX, as it inhibits the reducing activity of TRX by interacting with the catalytic active center of TRX [3,4]. TXNIP expression is induced by various stress conditions and controls various cellular phenotypes by directly or indirectly regulating the signaling pathways [5,6].
Studies have elucidated the role of ROS and oxidative stress in regulating hematopoiesis . Hematopoietic stem cells (HSCs) reside in specialized niches that are dependent on ROS levels. A low level of ROS is important for quiescence, and a higher level of ROS promotes the differentiation, proliferation, migration, and survival of HSCs and progenitor cells [8▪]. High levels of ROS can result in abnormal hematopoiesis, and hematopoietic cells appear to be particularly vulnerable to oxidative stress [9–11]. Recently, we identified an antioxidant function of TXNIP in hematopoietic cells or immune cells that differs from the conventional pro-oxidant action of TXNIP that has been demonstrated in other cell types. We therefore found a context-dependent function of TXNIP under oxidative stress, suggesting a different function of TXNIP in the hematopoietic redox system through its interaction with other redox regulatory proteins [12,13▪▪,14▪].
In this review, we focus on the recent findings of the regulation and cellular functions of ROS in hematopoietic cells. In particular, we discuss the activity of TXNIP in hematopoiesis via a context-dependent redox regulatory mechanism under oxidative stress conditions.
GENERAL FEATURES OF THIOREDOXIN-INTERACTING PROTEIN
TXNIP, which is also known as vitamin D3 upregulated protein 1 (VDUP-1) or thioredoxin-binding protein 2 (TBP-2), was originally reported in 1994 as a gene upregulated in HL-60 cells treated with vitamin D3. TXNIP has been shown to be a negative regulator of TRX function by inhibiting the reducing activity of TRX via its interaction with the catalytic active center of TRX [3,4]. TXNIP is a highly conserved protein and has close sequence homology between the human and mouse protein (94%) [4,15]. The human TXNIP gene is located on chromosome 1q21.1, contains 8 exons, and is 4174 bp in length . TXNIP is a 391-amino acid, 46-kDa protein that has two arrestin-like domains and belongs to the α-arrestin protein family [17–19]. The PPXY motifs of TXNIP are then targeted by the E3 ubiquitin ligase, ITCH, mediating proteasomal degradation [20,21]. TXNIP expression is induced by chemicals, including vitamin D3 , suberoylanilide hydroxamic acid (SAHA) , and 5-fluorouracil ; deprivation or addition of interleukin-2 in cell culture ; carcinogens ; and various stress conditions, such as high glucose, H2O2, transforming growth factor-β, ultraviolet light, heat shock, and mechanical stress [5,6].
We and others have also reported the various functions of TXNIP in vitro and in vivo. For instance, TXNIP directly interacts with jun-activation domain-binding protein-1 (JAB1) and increases p27(kip1) stability by inhibiting JAB1 . In vivo, TXNIP has been shown to be a critical factor for the development and function of NK cells by regulating the expression of CD122 . TXNIP associates with the beta-domain of pVHL, thereby enhancing the interaction between pVHL and hypoxia-inducible factor (HIF)1alpha, and promoting the nuclear export and degradation of HIF1alpha in a hypoxia-independent manner . TXNIP has been found to inhibit NF-KB activity via an association with histone deacetylase (HDAC)1 and HDAC3 , and to activate the inflammasome via an interaction with an NLRP3 component . TXNIP aggravates bacteremic shock by regulating the phosphatidylinositide 3-kinase (PI3K) pathway in macrophages, and increased production of ROS by the peritoneal cells of TXNIP-deficient mice promotes bacterial clearance . TXNIP interacts with p53 and regulates intracellular ROS levels by inducing p53 activity in hematopoietic cells [13▪▪]. TXNIP links nitric oxide synthesis and NLRP3 inflammasome activation during endotoxic shock; in the absence of TXNIP, endotoxic shock is exacerbated because of excessive nitric oxide synthesis [14▪]. TXNIP regulates the localization of TRX-1 under nitrosative and oxidative stress conditions by activating the ERK1/2 mitogen-activated protein kinases (MAPKs) . Recently, our colleagues demonstrated the structural basis for the direct interaction between TXNIP and TRX, showing the dissociation of the intermolecular disulfide bond in the presence of high concentrations of ROS [32▪].
As discussed above, TXNIP has diverse functions in cellular signaling pathways and has emerged as a critical regulator of the oxidative stress response. Interestingly, our recent data showed an antioxidant function of TXNIP in hematopoietic cells or immune cells, and this function differs from the conventional pro-oxidant activity of TXNIP demonstrated in other cell types under oxidative stress [12,13▪▪,14▪].
THIOREDOXIN-INTERACTING PROTEIN IN OXIDATIVE STRESS
The cellular redox system regulates the signaling pathways, resulting in cellular activation, differentiation, proliferation, and apoptosis . To maintain the redox balance, eukaryotic cells have antioxidant molecules, such as glutathione, TRX-1 and TRX-2, and glutaredoxin .
The TRX system is highly conserved in almost all species from bacteria to higher eukaryotes [35,36]. TRX plays an important role in cellular signaling by participating in sulfhydryl reactions (e.g., reducing cysteine residues) and by interacting with various components of signaling pathways [1,2]. TRX is induced and secreted from cells in response to oxidative stress; therefore, serum and plasma levels of TRX are considered a good marker of oxidative stress [5,37].
TXNIP has recently received considerable attention because of its involvement in redox signaling as an endogenous inhibitor of TRX [6,36]. TRX regulates the cellular redox state by reducing oxidized cysteine residues in the TRX catalytic core, resulting in the oxidization of TRX and reduction of residues on target proteins [19,34]. TXNIP binds TRX and acts as a competitive inhibitor, removing TRX from proteins that are negatively impacted by the steric effect of TRX-1 binding, such as apoptosis signal-regulating kinase 1 (ASK1) [34,38]. The expression of TXNIP is upregulated by factors such as disturbed blood flow and high glucose, resulting in reduced TRX reductase activity [39–41].
Recent studies investigating the crystal structure of the TRX–TXNIP complex have shown that the inhibition of TRX by TXNIP is mediated by an intermolecular disulfide-bond-switching mechanism. Upon binding to TRX, TXNIP undergoes a structural rearrangement that involves the switching of a head-to-tail interprotomer Cys63–Cys247 disulfide bond between TXNIP molecules to an interdomain Cys63–Cys190 disulfide bond and the formation of a de-novo intermolecular TXNIP Cys247–TRX Cys32 disulfide bond. Furthermore, a dissociation of the intermolecular disulfide bond was observed between TRX and TXNIP in the presence of oxidative stress [32▪]. ERK1/2 MAP K activation and spatial distribution within cells trigger TRX-1 nuclear translocation by downregulating TXNIP under oxidative stress . TXNIP mediates high-glucose-induced ROS generation by mitochondria and the NADPH oxidase Nox4 in mesangial cells . TXNIP has marked antiproliferative effects in smooth muscle cells through the suppression of TRX activity, suggesting that the regulation of TXNIP is a critical molecular switch in the transduction of pro-oxidant mitogenic signals . The TXNIP–TRX1 complex enables inflammation by promoting endothelial cell survival and vascular endothelial growth factor signaling under conditions of physiological oxidative stress . Downregulation or overexpression of TXNIP regulates apoptosis and cell survival under conditions of oxidative stress in cells, and these effects involve the inhibition or activation of ASK1 activity [44,45]. The inhibition of TRX-mediated antioxidant function by TXNIP induces ROS and results in cellular aging, apoptosis, growth arrest, and disease [46,47].
Recently, we demonstrated an elevated level of ROS in Txnip–/– immune cells or hematopoietic cells under oxidative stress. Peritoneal cells from Pseudomonas aeruginosa-infected TXNIP-deficient mice produced more ROS than those of infected wildtype mice . ROS levels were elevated and induced apoptosis in Txnip–/– hematopoietic cells. Loss of TXNIP led to a dramatic induction of apoptosis in hematopoietic cells under oxidative stress. TXNIP regulated intracellular ROS levels via the p53-induced expression of antioxidant genes [13▪▪]. We also found the same phenomenon in a model of lipopolysaccharide (LPS)-induced oxidative stress in Txnip–/– macrophages. Txnip–/– mice were more susceptible to LPS-induced endotoxic shock. Txnip–/– macrophages produced significantly higher levels of nitric oxide, and an inducible nitric oxide synthase (iNOS) inhibitor rescued Txnip–/– mice from LPS-induced death, demonstrating that nitric oxide was a major factor in LPS-induced oxidative stress [14▪].
HEMATOPOIETIC STEM CELLS IN OXIDATIVE STRESS
HSCs are mostly quiescent and cytokine resistant, and have low metabolic activity, but long-term dysregulated accumulation of ROS in HSCs leads to abnormal hematopoiesis [48–50]. A low level of ROS is important for quiescent HSCs to maintain their stemness, whereas a higher level of ROS within HSCs or within the HSC niche promotes differentiation, proliferation, migration, and survival of HSCs or progenitor cells [8▪]. Recent studies suggest that long-term repopulating cells reside in close proximity to the endosteal surface of the bone, a site of low oxygen tension and hypoxia . As low levels of ROS accumulation are maintained under hypoxic conditions, and the generation of ROS is essential for the activation of the hypoxic response [52,53], ROS may be directly involved in the regulation of HSC niche interactions . HSCs generate energy mainly via anaerobic metabolism by maintaining a high rate of glycolysis. This metabolic balance helps maintain HSCs by limiting the production of ROS but renders HSCs more susceptible to changes in redox status .
A number of studies have revealed the relationship between HSCs and ROS in vitro and in vivo. Atm–/– mice older than 24 weeks have progressive bone marrow failure because of a defect in HSC function, a function that was associated with elevated ROS . Activation of p38 MAPK in response to ROS limits the lifespan of HSCs in Atm–/– mice, and elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in HSC quiescence . ROS regulatory genes were decreased in Forkhead box O (FOXO)-deficient HSCs, and in-vivo treatment with the antioxidant agent, N-acetyl-l-cysteine (NAC) resulted in reversion of the FOXO-deficient HSC phenotype . Parp1–/– mice have no defects in hematopoiesis, but oxidative stress compromises the repopulating capacity of Parp1–/– HSCs in transplanted recipient mice . Overexpression of Bmi1 confers resistance to oxidative stress in HSCs and enhances their regenerative capacity .
Meis1 deletion leads to the accumulation of ROS in HSCs and decreased expression of genes implicated in the hypoxic response . DJ-1, one of the genes responsible for Parkinson's disease, directly binds to mortalin and acts as a negative regulator of ROS in HSCs . A role for Wnt5a in the regulation of HSC quiescence and hematopoietic repopulation through the Ryk receptor by suppression of ROS has been proposed .
HEMATOPOIESIS UNDER OXIDATIVE STRESS
In hematopoietic cells, ROS levels are important modulators of cellular differentiation in both physiologic and pathologic conditions. Excessive ROS levels can result in abnormal hematopoiesis and promote conditions such as anemia and hematopoietic cell malignancies [9–11]. It is also known that cytokine signaling in hematopoietic cells is accompanied by ROS generation [63,64]. Thus, ROS play a direct role not only in the regulation of HSCs, but also in hematopoiesis.
Several recent reports support the role of ROS in the regulation of hematopoiesis under oxidative stress. Platelets released from mature mouse megakaryocytes may be ROS dependent . Ionizing radiation induces intracellular ROS and promotes phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation in CD41-expressing cells. The enhanced differentiation was regulated through ERK1/2 and p38 MAPKs by regulating heme oxygenase-1 (HO1) . The intracellular response to oxidative stress in erythropoiesis involves Forkhead box O3a (FOXO3), which controls the pathways regulating erythroid maturation and levels of oxidative stress during murine erythropoiesis. Inhibition of Akt by resveratrol results in FOXO3 activation and renders pathological erythroid precursors resistant to oxidative stress and continued differentiation .
Increased ROS production has been related to the progression of myeloid malignancies, such as chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) . NUP98–HOXD13 (NHD13) transgenic mice, a murine model of the myelodysplastic syndromes (MDS), showed increased levels of ROS in bone marrow nucleated cells (BMNCs), increased DNA double-strand breaks, and activation of the G2/M cell cycle checkpoint. These results suggest that oxidative stress may contribute to the progression of MDS to AML .
We investigated the antioxidant function of TXNIP in hematopoietic cells from Txnip–/– mice. Aged Txnip–/– mice exhibited elevated ROS levels in HSCs and reduced numbers of HSCs. Txnip–/– mice showed decreased expression of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into TxnipV bone marrow cells rescued HSC numbers and greatly increased survival in mice following oxidative stress. TXNIP is a regulator of p53 and plays a pivotal role in the maintenance of hematopoietic cells by regulating intracellular ROS during oxidative stress [13▪▪].
Current studies support the role of TXNIP in diverse biological functions. Recently, TXNIP has emerged as a critical regulator of the oxidative stress response via TRX-dependent and TRX-independent mechanisms. The regulation of ROS is important for HSC maintenance and hematopoiesis. Our recent findings have revealed that the activity of TXNIP is context dependent under oxidative stress conditions and that TXNIP potentially has a different function in hematopoietic cells because of a direct interaction with other redox regulatory proteins (Fig. 1). The studies of TXNIP in hematopoietic cells suggest that TXNIP is a key antioxidant protein and plays a pivotal role in the maintenance of hematopoietic cells under oxidative stress.
This work was supported in part by the grants from the GRL project and the New Drug Target Discovery Project (M10848000352-08N4800-35210), the Ministry of Education, Science & Technology, the Korean Health Technology R&D Project (A121934), and KRIBB Research Initiative Program, Republic of Korea.
Conflicts of interest
There are no conflicts of interest.
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