Papers by Christopher Horst Lillig
Free Radical Biology and Medicine, 2020
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BIOCELL, 2011
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PLOS ONE, 2015
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Proceedings of the National Academy of Sciences, 2014
Significance Inflammation often complicates diseases associated with oxidative stress. This study... more Significance Inflammation often complicates diseases associated with oxidative stress. This study shows that inflammatory macrophages release proteins with specific forms of cysteine oxidation to disulfides, particularly glutathionylation. Redox proteomics identified peroxiredoxin 2 (PRDX2) as a protein released in glutathionylated form by inflammation both in vivo and in vitro. Extracellular PRDX2 then triggers the production of TNF-α. These data indicate that redox-dependent mechanisms, in an oxidative cascade, can induce inflammation.
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Journal of Biological Chemistry, 2013
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Glutaredoxins catalyze glutathione-dependent thiol disulfide oxidoreductions via a GSH-binding si... more Glutaredoxins catalyze glutathione-dependent thiol disulfide oxidoreductions via a GSH-binding site and active cysteines. Recently a second human glutaredoxin (Grx2), which is targeted to either mitochondria or the nucleus, was cloned. Grx2 contains the active site sequence CSYC, which is different from the conserved CPYC motif present in the cytosolic Grx1. Here we have compared the activity of Grx2 and Grx1 using glutathionylated substrates and active site mutants. The kinetic studies showed that Grx2 catalyzes the reduction of glutathionylated substrates with a lower rate but higher affinity compared with Grx1, resulting in almost identical catalytic efficiencies (k cat/K m). Permutation of the active site motifs of Grx1 and Grx2 revealed that the CSYC sequence of Grx2 is a prerequisite for its high
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The FASEB Journal
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Oxidative Medicine and Cellular Longevity, 2021
The mammalian cytosolic thioredoxin (Trx) system consists of Trx1 and its reductase, the NADPH-de... more The mammalian cytosolic thioredoxin (Trx) system consists of Trx1 and its reductase, the NADPH-dependent seleno-enzyme TrxR1. These proteins function as electron donor for metabolic enzymes, for instance in DNA synthesis, and the redox regulation of numerous processes. In this work, we analysed the interactions between these two proteins. We proposed electrostatic complementarity as major force controlling the formation of encounter complexes between the proteins and thus the efficiency of the subsequent electron transfer reaction. If our hypothesis is valid, formation of the encounter complex should be independent of the redox reaction. In fact, we were able to confirm that also a redox inactive mutant of Trx1 lacking both active site cysteinyl residues (C32,35S) binds to TrxR1 in a similar manner and with similar kinetics as the wild-type protein. We have generated a number of mutants with alterations in electrostatic properties and characterised their interaction with TrxR1 in ki...
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Thioredoxins (Trxs) provide electrons to essential cellular processes such as DNA synthesis. Here... more Thioredoxins (Trxs) provide electrons to essential cellular processes such as DNA synthesis. Here, we characterize human and murine Trx1 as new iron-sulfur proteins. The [2Fe-2S] cluster is complexed using cysteinyl side chains 32 and 73 in a dimeric holocomplex. Formation of the holo-dimer depends on small structural changes of the loop connecting helices three and four and is stabilized by the formation of a direct electrostatic interaction between Lys72 and Asp60 of two monomers. The not strictly conserved Cys73 in vertebrates co-evolved with the regulation of cellular iron homeostasis through the iron-regulatory proteins (IRP). Active apo-Trx1 is required for the reduction of cysteinyl residues in IRP1 and its binding to the iron-responsive elements in the mRNA encoding hypoxiainducible factor (HIF) 2α. Depletion of Trx1 increased the mRNA levels of HIF2α, an important target of IRP1. Hence, translation of the HIF2α mRNA requires either sufficient iron-supply or the lack of redu...
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Redox Regulation of Differentiation and De-Differentiation
Cysteine, the predominant biological thiol, was identified in 1884. Its presence in living organi... more Cysteine, the predominant biological thiol, was identified in 1884. Its presence in living organisms and the biochemistry of reduction and oxidation as well the importance of the redox state for protein function was elucidated in the first half of the 20th century. In the second half, proteins regulating the thiol redox state were identified, especially proteins facilitating or maintaining thiols reduced. Numerous posttranslational thiol modifications are described. This chapter provides a brief overview of the research on thiol redox regulation and is intended to remind researchers that knowledge of the history of a research field is helpful in pointing out that observations considered novel may already have been described years ago.
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Free radical biology & medicine, Jan 9, 2015
Peripheral nerve injury causes redox stress in injured neurons by upregulations of pro-oxidative ... more Peripheral nerve injury causes redox stress in injured neurons by upregulations of pro-oxidative enzymes, but most neurons survive suggesting an activation of endogenous defense against the imbalance. As potential candidates we assessed thioredoxin-fold proteins, called redoxins, which maintain redox homeostasis by reduction of hydrogen peroxide or protein dithiol-disulfide exchange. Using a histologic approach, we show that the peroxiredoxins (Prdx1-6), the glutaredoxins (Glrx1, 2, 3 and 5), thioredoxin (Txn1 and 2) and their reductases (Txnrd1 and 2) are expressed in neurons, glial and/or vascular cells of the dorsal root ganglia (DRGs) and in the spinal cord. They show distinct cellular and subcellular locations in agreement with the GO terms for "cellular component". The expression and localization of Glrx, Txn and Txnrd proteins was not affected by sciatic nerve injury but peroxiredoxins were upregulated in the DRGs, Prdx1 and Prdx6 mainly in non-neuronal cells and Pr...
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Redox Regulation of Differentiation and De-Differentiation
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Microscopy and Microanalysis
Summary:Thioredoxin Family of proteins as Thioredoxin (Trxs), Glutaredoxins (Grxs) and Peroxiredo... more Summary:Thioredoxin Family of proteins as Thioredoxin (Trxs), Glutaredoxins (Grxs) and Peroxiredoxins (Prxs) are one of the most important agents in the defense of oxidative stress and redox regulation. Perinatal asphyxia (AP) a disorder generated at the expense of the deficit of oxygen associated or not to ischemia, affects 5 to 10 of every 1,000 live births in developing country and is a serious health problem worldwide. Alterations in antioxidant protection systems are involved in the pathogenesis of hypoxic-ischemic insult and neuronal death. For these reasons it is proposed that the AP can cause changes in the distribution and expression of antioxidant proteins and enhance their deleterious or neuroprotective effects on the CNS. Methods: to determine the implication of the proteins role induced in the hypoxic brain injury, an animal model in vivo of PA was used in this work. In the first instance, the identification of the distribution of Trxs family proteins Trx1, Trx2...
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Nature Communications
Despite their very close structural similarity, CxxC/S-type (class I) glutaredoxins (Grxs) act as... more Despite their very close structural similarity, CxxC/S-type (class I) glutaredoxins (Grxs) act as oxidoreductases, while CGFS-type (class II) Grxs act as FeS cluster transferases. Here we show that the key determinant of Grx function is a distinct loop structure adjacent to the active site. Engineering of a CxxC/S-type Grx with a CGFS-type loop switched its function from oxidoreductase to FeS transferase. Engineering of a CGFS-type Grx with a CxxC/S-type loop abolished FeS transferase activity and activated the oxidative half reaction of the oxidoreductase. The reductive half-reaction, requiring the interaction with a second GSH molecule, was enabled by switching additional residues in the active site. We explain how subtle structural differences, mostly depending on the structure of one particular loop, act in concert to determine Grx function.
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Metallothioneins and Related Chelators, 2015
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Pneumologie, 2012
Methods: To investigate individual functions of selected redoxins, an initial screen for general ... more Methods: To investigate individual functions of selected redoxins, an initial screen for general distribution comparing control-and inflamed mouse lungs (OVAlbumin sensitization and challenge) was performed. For characterisation of the protein of interest, we purified a broad set of redoxins and intraperitoneal injection of 40µg/day was done on 5 consecutive days starting two days before challenge. Evaluation of the allergic phenotype in balb/c mice focussed on the analysis of airway hyperreactivity, infiltrating inflammatory cells and ...
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Pneumologie, May 31, 2012
Methods: To investigate individual functions of selected redoxins, an initial screen for general ... more Methods: To investigate individual functions of selected redoxins, an initial screen for general distribution comparing control-and inflamed mouse lungs (OVAlbumin sensitization and challenge) was performed. For characterisation of the protein of interest, we purified a broad set of redoxins and intraperitoneal injection of 40µg/day was done on 5 consecutive days starting two days before challenge. Evaluation of the allergic phenotype in balb/c mice focussed on the analysis of airway hyperreactivity, infiltrating inflammatory cells and ...
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Histochemistry and Cell Biology
Ischemia and reperfusion events, such as myocardial infarction (MI), are reported to induce remot... more Ischemia and reperfusion events, such as myocardial infarction (MI), are reported to induce remote organ damage severely compromising patient outcomes. Tissue survival and functional restoration relies on the activation of endogenous redox regulatory systems such as the oxidoreductases of the thioredoxin (Trx) family. Trxs and peroxiredoxins (Prxs) are essential for the redox regulation of protein thiol groups and for the reduction of hydrogen peroxide, respectively. Here, we determined whether experimental MI induces changes in Trxs and Prxs in the heart as well as in secondary organs. Levels and localization of Trx1, TrxR1, Trx2, Prx1, and Prx2 were analyzed in the femur, vertebrae, and kidneys of rats following MI or sham surgery. Trx1 levels were significantly increased in the heart (P = 0.0017) and femur (P
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Free Radical Biology and Medicine
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Biochemical Society Transactions
Processing of and responding to various signals is an essential cellular function that influences... more Processing of and responding to various signals is an essential cellular function that influences survival, homeostasis, development, and cell death. Extra- or intracellular signals are perceived via specific receptors and transduced in a particular signalling pathway that results in a precise response. Reversible post-translational redox modifications of cysteinyl and methionyl residues have been characterised in countless signal transduction pathways. Due to the low reactivity of most sulfur-containing amino acid side chains with hydrogen peroxide, for instance, and also to ensure specificity, redox signalling requires catalysis, just like phosphorylation signalling requires kinases and phosphatases. While reducing enzymes of both cysteinyl- and methionyl-derivates have been characterised in great detail before, the discovery and characterisation of MICAL proteins evinced the first examples of specific oxidases in signal transduction. This article provides an overview of the funct...
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Papers by Christopher Horst Lillig