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1.
Human Cysteine Cathepsins Degrade Immunoglobulin G In Vitro in a Predictable Manner.
Høglund, RA, Torsetnes, SB, Lossius, A, Bogen, B, Homan, EJ, Bremel, R, Holmøy, T
International journal of molecular sciences. 2019;(19)
Abstract
Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology.
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2.
Role of Glutathionylation in Infection and Inflammation.
Checconi, P, Limongi, D, Baldelli, S, Ciriolo, MR, Nencioni, L, Palamara, AT
Nutrients. 2019;(8)
Abstract
Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.
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3.
Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children.
Alvarez, JA, Grunwell, JR, Gillespie, SE, Tangpricha, V, Hebbar, KB
The Journal of steroid biochemistry and molecular biology. 2018;:164-169
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Abstract
Critically ill populations incur high levels of oxidative stress and commonly present with vitamin D deficiency. This study aimed to investigate the relationship between vitamin D status and plasma markers of glutathione (GSH) and cysteine (Cys) redox and immunity in critically ill children. This was a cross-sectional study of n=50 PICU patients. Subjects were categorized according to their plasma 25-hydroxyvitamin D [25(OH)D] concentrations: (<20, 20-30, and ≥30ng/dL). Plasma GSH, glutathione disulfide (GSSG), Cys, and cystine (CySS) were measured with high-performance liquid chromatography, and their associated redox potentials determined (EhGSSG and EhCySS, respectively). Plasma LL-37, an indicator of innate immune function, was assayed with ELISA. Data were analyzed using general linear regression before and after adjustment for age, sex, and race. Results showed that EhCySS was more reduced in subjects with plasma 25(OH)D concentrations ≥30ng/mL compared to those with 25(OH)D concentrations <20ng/mL (P=0.009). Plasma GSH, GSSG, and total GSH decreased with increasing 25(OH)D category (P=0.06, 0.03, and 0.01, respectively), and plasma glutamine levels were lowest in subjects with plasma 25(OH)D concentrations ≥30ng/mL (P=0.004). Plasma LL-37 concentrations did not significantly differ by vitamin D status (P=0.08). In conclusion, vitamin D sufficiency was associated with more reduced plasma EhCySS, indicative of lower oxidative stress in critically ill children. Plasma GSH, GSSG, and glutamine, however, were lower in the vitamin D sufficient group. The role of vitamin D in maintaining redox status during pediatric critical illness requires further study.
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iPreny-PseAAC: Identify C-terminal Cysteine Prenylation Sites in Proteins by Incorporating Two Tiers of Sequence Couplings into PseAAC.
Xu, Y, Wang, Z, Li, C, Chou, KC
Medicinal chemistry (Shariqah (United Arab Emirates)). 2017;(6):544-551
Abstract
BACKGROUND Occurring at the cysteine residue in the C-terminal of a protein, prenylation is a special kind of post-translational modification (PTM), which may play a key role for statin in altering immune function. Therefore, knowledge of the prenylation sites in proteins is important for drug development as well as for in-depth understanding the biological process concerned. OBJECTIVE Given a query protein whose C-terminal contains some cysteine residues, which one can be of prenylation or none of them can be prenylated? METHODS To address this problem, we have developed a new predictor, called "iPreny-PseAAC", by incorporating two tiers of sequence pair coupling effects into the general form of PseAAC (pseudo amino acid composition). RESULTS It has been observed by four different cross-validation approaches that all the important indexes in reflecting its prediction quality are quite high and fully consistent to each other. CONCLUSION It is anticipated that the iPreny-PseAAC predictor holds very high potential to become a useful high throughput tool in identifying protein C-terminal cysteine prenylation sites and the other relevant areas. To maximize the convenience for most experimental biologists, the webserver for the new predictor has been established at http://app.aporc.org/iPreny-PseAAC/, by which users can easily get their desired results without needing to go through the mathematical details involved in this paper.
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Cysteine-rich low molecular weight antimicrobial peptides from Brevibacillus and related genera for biotechnological applications.
Baindara, P, Kapoor, A, Korpole, S, Grover, V
World journal of microbiology & biotechnology. 2017;(6):124
Abstract
The production of natural antimicrobial peptides (AMPs) is an innate immunity trait of all life forms including eukaryotes and prokaryotes. While these AMPs are usually called as defensins in eukaryotes, they are known as bacteriocins in prokaryotes. Bacteriocins are more diverse AMPs considering their varied composition and posttranslational modifications. Accordingly, this review is focused on cysteine-rich AMPs resembling eukaryotic defensins such as laterosporulin from Brevibacillus spp. and associated peptides secreted by the members of related genera. In fact, structural studies of laterosporulin showed the pattern typically observed in human defensins and therefore, should be considered as bacterial defensin. Although the biosynthesis mechanism of bacterial defensins displayed high similarities, variations in amino acid composition and structure provided the molecular basis for a better understanding of their properties. They are reported to inhibit Gram-positive, Gram-negative, non-multiplying and human pathogenic bacteria. The extreme stability is due to the presence of intra-molecular disulfide bonds in prokaryotic defensins and reveals their potential clinical and food preservation applications. Notably, they are also reported to have potential anticancer properties. Therefore, this review is focused on multitude of diverse applications of bacterial defensins, exploring the possible correlations between their structural, functional and possible biotechnological applications.
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An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly.
McCarty, MF, DiNicolantonio, JJ
Age (Dordrecht, Netherlands). 2015;(5):96
Abstract
Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly. Increased efficiency of protein translation reflecting increased leucine intake and consequent greater mTORC1 activity may play a role in this effect; however, at present there is little solid evidence that leucine supplementation provides important long-term benefits to the elderly. Aside from its potential pro-anabolic impact, higher dietary protein intakes may protect the elderly in another way-by providing increased amino acid substrate for synthesis of key protective factors. There is growing evidence, in both rodents and humans, that glutathione synthesis declines with increasing age, likely reflecting diminished function of Nrf2-dependent inductive mechanisms that boost expression of glutamate cysteine ligase (GCL), rate-limiting for glutathione synthesis. Intracellular glutathione blunts the negative impact of reactive oxygen species (ROS) on cell health and functions both by acting as an oxidant scavenger and by opposing the pro-inflammatory influence of hydrogen peroxide on cell signaling. Fortunately, since GCL's K m for cysteine is close to intracellular cysteine levels, increased intakes of cysteine-achieved from whole proteins or via supplementation with N-acetylcysteine (NAC)-can achieve a compensatory increase in glutathione synthesis, such that more youthful tissue levels of this compound can be restored. Supplementation with phase 2 inducers-such as lipoic acid-can likewise increase glutathione levels by promoting increased GCL expression. In aging humans and/or rodents, NAC supplementation has exerted favorable effects on vascular health, muscle strength, bone density, cell-mediated immunity, markers of systemic inflammation, preservation of cognitive function, progression of neurodegeneration, and the clinical course of influenza-effects which could be expected to lessen mortality and stave off frailty. Hence, greater cysteine availability may explain much of the favorable impact of higher protein intakes on mortality and frailty risk in the elderly, and joint supplementation with NAC and lipoic acid could be notably protective in the elderly, particularly in those who follow plant-based diets relatively low in protein. It is less clear whether the lower arginine intake associated with low-protein diets has an adverse impact on vascular health.
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7.
Cysteine and cysteine-related signaling pathways in Arabidopsis thaliana.
Romero, LC, Aroca, MÁ, Laureano-Marín, AM, Moreno, I, García, I, Gotor, C
Molecular plant. 2014;(2):264-76
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Abstract
Cysteine occupies a central position in plant metabolism because it is a reduced sulfur donor molecule involved in the synthesis of essential biomolecules and defense compounds. Moreover, cysteine per se and its derivative molecules play roles in the redox signaling of processes occurring in various cellular compartments. Cysteine is synthesized during the sulfate assimilation pathway via the incorporation of sulfide to O-acetylserine, catalyzed by O-acetylserine(thiol)lyase (OASTL). Plant cells contain OASTLs in the mitochondria, chloroplasts, and cytosol, resulting in a complex array of isoforms and subcellular cysteine pools. In recent years, significant progress has been made in Arabidopsis, in determining the specific roles of the OASTLs and the metabolites produced by them. Thus, the discovery of novel enzymatic activities of the less-abundant, like DES1 with L-cysteine desulfhydrase activity and SCS with S-sulfocysteine synthase activity, has provided new perspectives on their roles, besides their metabolic functions. Thereby, the research has been demonstrated that cytosolic sulfide and chloroplastic S-sulfocysteine act as signaling molecules regulating autophagy and protecting the photosystems, respectively. In the cytosol, cysteine plays an essential role in plant immunity; in the mitochondria, this molecule plays a central role in the detoxification of cyanide, which is essential for root hair development and plant responses to pathogens.
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Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction.
Lockwood, TD
Metallomics : integrated biometal science. 2013;(2):110-24
Abstract
In the 1930's pioneers discovered that maximal autolysis in tissue homogenates requires metal chelator, sulfhydryl reducing agent and acid pH. However, metals, reducing equivalents and protons (MR&P) have been overlooked as combined catalytic controls. Three categories of lysosomal machinery drive three distinguishable cycles importing and exporting MR&P. Zn(2+) preemptively inhibits CysHis catalysis under otherwise optimal protonation and reduction. Protein-bound cell Zn(2+) concentration is 200-2000 times the non-sequestered inhibitory concentration. Following autophagy, lysosomal proteolysis liberates much inhibitory Zn(2+). The vacuolar proton pump is the driving force for Zn(2+) export, as well as protonation of the peptidolytic mechanism. Other machinery of lysosomal cycles includes proton-driven Zn(2+) exporters (e.g. SLC11A1), Zn(2+) channels (e.g. TRPML-1), lysosomal thiol reductase, etc. The CysHis dyad is a sensor of the vacuolar environment of MR&P, an integrator of these simultaneous variables, and a catalytic responder. Rate-determination can shift between autophagic substrate acquisition (swallowing) and substrate degradation (digesting). Zn(2+) recycling from degraded proteins to new proteins is a fourth cycle that might pace lysosomal function under some conditions. Heritable insufficient or excess functions of CysHis cathepsins are associated with dysfunctional inflammation and immunity/auto-immunity, including diabetic pathogenesis.
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9.
Antioxidant supplements prevent oxidation of cysteine/cystine redox in patients with age-related macular degeneration.
Moriarty-Craige, SE, Adkison, J, Lynn, M, Gensler, G, Bressler, S, Jones, DP, Sternberg, P
American journal of ophthalmology. 2005;(6):1020-6
Abstract
PURPOSE Determine whether antioxidant supplements alter the plasma glutathione and/or cysteine redox potential in age-related macular degeneration (AMD) patients. DESIGN This was an ancillary study to the Age-Related Eye Disease Study (AREDS), where subset of AREDS subjects at two sites were studied at two time points, an average of 1.7 and 6.7 years after enrollment. METHODS Plasma glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), and cystine (CySS) were measured by high-performance liquid chromatography, and redox potentials of GSH/GSSG (E(h) GSH) and Cys/CySS (E(h) Cys) were calculated. The means of the metabolites and redox potentials were compared by repeated-measures analysis of variance for subjects receiving antioxidants and those not receiving antioxidants. RESULTS At the first blood draw, the means for the antioxidant group (n = 153) and no antioxidant group (n = 159) were not significantly different for any of the metabolites or redox potentials. At the second draw, the GSH parameters were not significantly different between the antioxidant (n = 37) and no antioxidant (n = 45) groups; however, mean Cys was significantly higher in the antioxidant group (9.5 vs 7.2 micromol/l, P = .008). Also, mean E(h) Cys was significantly more reduced in the antioxidant group (-74 vs -67.3 mV, P = .03). CONCLUSIONS The AREDS antioxidant supplements reduced oxidation of E(h) Cys but had no effect on GSH. Because Cys is important for cell growth, apoptosis, and immune function, the beneficial effect of antioxidant supplementation on progression to advanced AMD may be partially explained by its effect on E(h) Cys and/or its effect on Cys availability.