The Intracellular Proteolytic Processing of Extracellular Superoxide Dismutase (EC-SOD) is a Two-step Event

Olsen, Dorte Aalund; Petersen, Steen V.; Oury, Tim D.; Valnickova, Zuzana; Thøgersen, Ida B.; Kristensen, Torsten Nygaard; Bowler, R.P.; Crapo, James D.; Enghild, Jan J.

doi:10.1074/jbc.m401180200

Cited by 47 publications

(32 citation statements)

References 31 publications

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“…39,40 Our fluorescence cell sorting analysis showed that acute deletion of SOD3 leads to a striking pulmonary infiltration of various inflammatory cells. Among T cell subtypes, the increase in CD8 ϩ cells was greater than CD4 ϩ cells.…”

Section: Discussionmentioning

confidence: 99%

Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air

Góngora

Lob

Landmesser

et al. 2008

The American Journal of Pathology

113

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The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3 ؊/؊ mice compared with either mice with acute SOD3 reduction or wildtype controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe

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Section: Discussionmentioning

confidence: 99%

Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air

Góngora

Lob

Landmesser

et al. 2008

The American Journal of Pathology

113

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“…The intracellular pool of EC-SOD was enriched from cells transiently expressing wild-type EC-SOD. Cells were washed with Hanks' balanced salt solution; lysed by the addition of 25 mM Tris-HCl, 1 M NaCl, 0.5% (v/v) Triton X-100, and 5 mM EDTA (pH 7.4) containing 1 mM phenylmethylsulfonyl fluoride; and purified by immunoaffinity chromatography using a monoclonal antibody directed against human EC-SOD (16). Protein was eluted using 0.1 M glycine (pH 2.7), and fractions were immediately neutralized by the addition of 1 M TrisHCl (pH 8.0).…”

Section: Methodsmentioning

confidence: 99%

The Folding of Human Active and Inactive Extracellular Superoxide Dismutases Is an Intracellular Event

Petersen

Kristensen

Petersen

et al. 2008

Journal of Biological Chemistry

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Human extracellular superoxide dismutase (EC-SOD) is a tetrameric glycoprotein responsible for the removal of superoxide generated in the extracellular space. Two different folding variants of EC-SOD exist based on the disulfide bridge connectivity, resulting in enzymatically active (aEC-SOD) and inactive (iEC-SOD) subunits. As a consequence of this, the assembly of the EC-SOD tetramers produces molecules with variable activity and may represent a way to regulate the antioxidant level in the extracellular space. To determine whether the formation of these two folding variants is an intra-or extracellular event, we analyzed the biosynthesis in human embryonic kidney 293 cells expressing wild-type EC-SOD. These analyses revealed that both folding variants were present in the intra-and extracellular spaces, suggesting that the formation is an intracellular event. To further analyze the biosynthesis, we constructed mutants with the capacity to generate only aEC-SOD (C195S) or iEC-SOD (C45S). The expression of these suggested that the cellular biosynthetic machinery supported the secretion of aEC-SOD but not iEC-SOD. The coexpression of these two mutants did not affect the expression pattern. This study shows that generation of the EC-SOD folding variants is an intracellular event that depends on a free cysteine residue not involved in disulfide bonding.

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“…Here we report a case-control association study which examined the possible role of candidate polymorphisms in the genes encoding the antioxidant enzymes copper-zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), extracellular superoxide dismutase (SOD3), and catalase (CAT). Specifically, we have targeted single nucleotide polymorphisms (SNPs) for their likely functional role: SOD1 +35 A/C which is located adjacent to a splice site, SOD2 Val16Ala which has been suggested to alter protein structure and function, 12 SOD3 213 (+760) C/G which has been shown to alter proteolytic processing, 13 and catalase 221 A/T which is located in the promoter region just proximal to the start site. 14 The SOD3 candidate polymorphism is of particular interest since the CRG substitution (+760) leads to an absence of cleaved SOD3 in the serum of carriers in a bimodal distribution.…”

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confidence: 99%

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function

Young

Black

Eddy

et al. 2006

Respiratory Medicine: COPD Update

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Background: Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function. Methods: In a case-control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD. Results: Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested. Conclusions: The 213Gly variant of the SOD3 gene may, through antioxidant or anti-inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.

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The Intracellular Proteolytic Processing of Extracellular Superoxide Dismutase (EC-SOD) is a Two-step Event

Cited by 47 publications

References 31 publications

Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air

Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air

The Folding of Human Active and Inactive Extracellular Superoxide Dismutases Is an Intracellular Event

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function

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