Zinc-mediated allosteric inhibition of caspase-6.

Velázquez-Delgado, Elih M.; Hardy, James L.

doi:10.1074/jbc.a112.397752

Cited by 14 publications

(26 citation statements)

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“…Thus, ZIP10 is a novel survival factor for B-cell progenitors and has a suppressive effect on caspase activity through Zn uptake. Although in vitro studies have previously demonstrated that physiological concentrations of Zn modulate caspase activity (31)(32)(33) cysteine residues in the catalytic domain of caspases inhibits their enzymatic activity (34), it was still elusive how Zn homeostasis modulates caspase-mediated apoptotic signaling in the physiological situation. It is well recognized that rigorous selection processes occur during B-cell maturation, in which down-regulation of the antiapoptotic factor B-cell lymphoma 2 (BCL2) induces apoptosis to prevent the generation and expansion of nonor self-reactive B-cell clones (19,35).…”

Section: Discussionmentioning

confidence: 99%

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

Miyai

Hojyo

Ikawa³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.B-lymphocyte | apoptosis | cytokine | bone marrow | zinc-signaling axis

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Section: Discussionmentioning

confidence: 99%

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

Miyai

Hojyo

Ikawa³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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“…This term describes downstream effects mediated through changes in gene expression, not signaling events. Importantly, intracellular zinc signaling targets a number of enzymes involved in cellular signaling, including protein tyrosine phosphatases (PTPs) (41, 448), phosphodiesterases (PDEs) (161, 427), calcineurin (14), caspases (285,423), and various kinases such as mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) (72, 149). Physiological levels of intracellular free Zn 2ϩ concentrations regulate these enzymes, e.g., inhibition of caspase-3, T-cell PTP, and PTP-1B is achieved with IC 50 values below 10, 200, and 17 nM, respectively (140, 266).…”

Section: Zinc Signalingmentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

848

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…Sulfenation could transiently or locally regulate caspase activity, since all caspases are cysteinyl proteases. While cellular Casp3 is under strong regulation by the inhibitor of apoptosis proteins 41 , Casp1 and Casp6 do not have known cellular protein inhibitors, although Casp6 can be inhibited in an allosteric fashion by phosphorylation and zinc 42,43 . The inhibition of Casp1, Casp3, and Casp6 could have a major influence on inflammation, apoptosis and neurodegeneration, respectively.…”

Section: Discussionmentioning

confidence: 99%

P1‐028: Methylene blue inhibits caspases by oxidation of the catalytic cysteine

Pakavathkumar

Sharma²,

Kaushal³

et al. 2015

Alzheimer's & Dementia

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Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.Methylene blue, a tricyclic phenothiazine (also known as methylthionine hydrochloride), has a history of diverse medical applications stretching over a century for treatment of enzymopenic hereditary methemoglobinemia, acute acquired methemoglobinemia, urinary tract infections, malaria, septic shock, and hepatopulmonary syndrome 1 . Alzheimer disease (AD) is a progressive neurodegenerative disorder showing abundant deposits of β -amyloid peptide (Aβ ) plaques, intracellular neurofibrillary tangles (NFTs) consisting of Tau protein, and the loss of synapses 2 . Presently, inhibitors of Tau aggregation are being considered as therapeutic interventions against AD, and methylene blue disaggregates Tau NFTs 3 . Methylene blue, and its demethylated derivatives azure A and azure B, were initially identified as blocking in vitro Tau-Tau aggregation identified as paired helical filaments by electron microscopy 3 . Methylene blue was also shown to prevent heparin-induced Tau filament formation 4 . More recently, several studies have demonstrated the ability of methylene blue to prevent Tau aggregation in transgenic mouse models expressing the P301L or P301S Tau mutations associated with the formation of NFTs in mice and in human disease. Treatment of the rTg4510 human P301L transgenic mouse with methylene blue improved behavior slightly in treated 3 month old mice, reduced brain total Tau and phospho-Tau, and increased neuronal survival 5 . However, treatments in 16 month old rTg4510 mice did not have any effect on Tau levels, neuronal survival or brain atrophy 6 . The preventative nature of methylene blue was also observed in Tau∆K280 and TauRDK transgenic mice where treatments started in 1.5 or 9 month old mice, but not in 15 month old mice, showed improved cognitive behavior and a decrease in pathological Tau at 18 mo...

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Zinc-mediated allosteric inhibition of caspase-6.

Abstract: PAGE 36002:Equation 2 was printed with mistakes. The correct equation is as follows:

Cited by 14 publications

References 0 publications

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

P1‐028: Methylene blue inhibits caspases by oxidation of the catalytic cysteine

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