Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

Božok, Valentina; Yu, Li-Ying; Palgi, Jaan; Arumäe, Urmas

doi:10.3389/fcell.2018.00106

Cited by 13 publications

(5 citation statements)

References 70 publications

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“…Whilst the antioxidant effects of the Trx system have been studied, the potential antioxidant properties of CXXC motifs in proteins outside of this system are less well understood. Recently, Cys to Ser site-directed mutagenesis of a CXXC motif in Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) demonstrated that the MANF CXXC motif provides protection from oxidative stress-induced apoptosis and reduces intracellular ROS [60]. This finding is similar to the data presented here and further supports an antioxidant role for the BCAT1 CXXC motif.…”

Section: Discussionsupporting

confidence: 87%

The BCAT1 CXXC Motif Provides Protection against ROS in Acute Myeloid Leukaemia Cells

et al. 2022

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The cytosolic branched-chain aminotransferase (BCAT1) has received attention for its role in myeloid leukaemia development, where studies indicate metabolic adaptations due to BCAT1 up-regulation. BCAT1, like the mitochondria isoform (BCAT2), shares a conserved CXXC motif ~10 Å from the active site. This CXXC motif has been shown to act as a ‘redox-switch’ in the enzymatic regulation of the BCAT proteins, however the response to reactive oxygen species (ROS) differs between BCAT isoforms. Studies indicate that the BCAT1 CXXC motif is several orders of magnitude less sensitive to the effects of ROS compared with BCAT2. Moreover, estimation of the reduction mid-point potential of BCAT1, indicates that BCAT1 is more reductive in nature and may possess antioxidant properties. Therefore, the aim of this study was to further characterise the BCAT1 CXXC motif and evaluate its role in acute myeloid leukaemia. Our biochemical analyses show that purified wild-type (WT) BCAT1 protein could metabolise H2O2 in vitro, whereas CXXC motif mutant or WT BCAT2 could not, demonstrating for the first time a novel antioxidant role for the BCAT1 CXXC motif. Transformed U937 AML cells over-expressing WT BCAT1, showed lower levels of intracellular ROS compared with cells over-expressing the CXXC motif mutant (CXXS) or Vector Controls, indicating that the BCAT1 CXXC motif may buffer intracellular ROS, impacting on cell proliferation. U937 AML cells over-expressing WT BCAT1 displayed less cellular differentiation, as observed by a reduction of the myeloid markers; CD11b, CD14, CD68, and CD36. This finding suggests a role for the BCAT1 CXXC motif in cell development, which is an important pathological feature of myeloid leukaemia, a disease characterised by a block in myeloid differentiation. Furthermore, WT BCAT1 cells were more resistant to apoptosis compared with CXXS BCAT1 cells, an important observation given the role of ROS in apoptotic signalling and myeloid leukaemia development. Since CD36 has been shown to be Nrf2 regulated, we investigated the expression of the Nrf2 regulated gene, TrxRD1. Our data show that the expression of TrxRD1 was downregulated in transformed U937 AML cells overexpressing WT BCAT1, which taken with the reduction in CD36 implicates less Nrf2 activation. Therefore, this finding may implicate the BCAT1 CXXC motif in wider cellular redox-mediated processes. Altogether, this study provides the first evidence to suggest that the BCAT1 CXXC motif may contribute to the buffering of ROS levels inside AML cells, which may impact ROS-mediated processes in the development of myeloid leukaemia.

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Section: Discussionsupporting

confidence: 87%

The BCAT1 CXXC Motif Provides Protection against ROS in Acute Myeloid Leukaemia Cells

et al. 2022

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“…Therefore, it is speculated that CXXC motifs may be associated with metal binding or with isomerase activity and oxidative refolding [21,32]. More importantly, a recent study has shown that the CXXC motifs of MANF inhibited programmed cell death [31]. All in all, the above research indicates that CXXC motifs of MANF may play a significant role in promoting survival.…”

Section: Molecular Structurementioning

confidence: 95%

“…Furthermore, MANF contains two CXXC motifs, which are highly conserved and belongs to cysteine motifs. Cysteine motifs are usually critical for the enzymes participating in disulfide isomerization or redox reactions [31]. Therefore, it is speculated that CXXC motifs may be associated with metal binding or with isomerase activity and oxidative refolding [21,32].…”

Section: Molecular Structurementioning

confidence: 99%

Potential Therapeutic Role and Mechanism of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Metabolic Disease

Ltd¹

2020

DWMJ

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Metabolic disease is a global epidemic and gradually became a serious public health problem, which comprised a few similar metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Metabolic diseases are characterized by the accumulation of abundant nutrients, subsequently induce glucolipotoxicity, intracellular stress, inflammation, and ultimately cell damage. Endoplasmic Reticulum stress (ER stress) exerts an important role in the pathogenesis of metabolic disease. ER stress could induce the inflammation and insulin resistance in adipocytes and hepatocytes, increase the apoptosis of pancreatic β cells and hepatocytes, and promote the gluconeogenesis and fatty acids synthesis. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) are the newly discovered Neurotrophic Factors (NTFs), which are firstly discovered for the neuroprotective functions. Both MANF and CDNF have a similar structure, but emerging evidence showed the prominent metabolic effect of MANF. MANF is also a secreted protein, located in the endoplasmic reticulum and ER stress would induce its expression and secretion. MANF is involved in food intake and the proliferation and survival of pancreatic β cells. Furthermore, MANF can protect hepatocyte against metabolic stress damage. Regards that the potential role of MANF in metabolic disease and ER stress, in this review, we summarized the molecular structure, physiological function and potential therapeutic role and mechanism of MANF in metabolic diseases.

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“…It should be noted that MANF’s protective activity by gene therapy in vitro was abolished with the deletion of the C-terminal RTDL domain, but the protein was biologically active and showed protective effects on ischemic stroke in vivo . Thus, only the C-terminal CxxC is essential for the neuroprotective activity of MANF in ischemic stroke in vivo ( Matlik et al, 2015 ) and antagonizes cell death ( Božok et al, 2018 ).…”

Section: Mesencephalic Astrocyte-derived Neurotrophic Factormentioning

confidence: 99%

UPR Responsive Genes Manf and Xbp1 in Stroke

Lõhelaid

Anttila

Liew

et al. 2022

Front. Cell. Neurosci.

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Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.

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Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

Cited by 13 publications

References 70 publications

The BCAT1 CXXC Motif Provides Protection against ROS in Acute Myeloid Leukaemia Cells

The BCAT1 CXXC Motif Provides Protection against ROS in Acute Myeloid Leukaemia Cells

Potential Therapeutic Role and Mechanism of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Metabolic Disease

UPR Responsive Genes Manf and Xbp1 in Stroke

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