The Serpin SQN-5 Is a Dual Mechanistic-Class Inhibitor of Serine and Cysteine Proteinases

Al-Khunaizi, May; Luke, Cliff J.; Askew, Yuko S.; Pak, Stephen C.; Askew, David J.; Çataltepe, Sule; Miller, David M.; Mills, David; Tsu, Christopher; Brὂmme, Dieter; Irving, James A.; Whisstock, James C.; Silverman, Gary A.

doi:10.1021/bi015999x

Cited by 61 publications

(55 citation statements)

References 41 publications

(72 reference statements)

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“…Thus, catL inhibition by high doses of a nuclear serpin (MENT or MNEI) may contribute to chromatin rearrangement in mature granulocytes. It is plausible to think that other closely related intracellular serpins, such as SCCA1, SQN-5, and Spi2A (1,33), that inhibit papain-like cysteine proteases may participate in controlling catL-mediated chromatin regulation in other cell types.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin

Bulynko

Hsing

Mason

et al. 2006

Molecular and Cellular Biology

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Posttranslational histone modifications and histone variants form a unique epigenetic landscape on mammalian chromosomes where the principal epigenetic heterochromatin markers, trimethylated histone H3(K9) and the histone H2A.Z, are inversely localized in relation to each other. Trimethylated H3(K9) marks pericentromeric constitutive heterochromatin and the male Y chromosome, while H2A.Z is dramatically reduced at these chromosomal locations. Inactivation of a lysosomal and nuclear protease, cathepsin L, causes a global redistribution of epigenetic markers. In cathepsin L knockout cells, the levels of trimethylated H3(K9) decrease dramatically, concomitant with its relocation away from heterochromatin, and H2A.Z becomes enriched at pericentromeric heterochromatin and the Y chromosome. This change is also associated with global relocation of heterochromatin protein HP1 and histone H3 methyltransferase Suv39h1 away from constitutive heterochromatin; however, it does not affect DNA methylation or chromosome segregation, phenotypes commonly associated with impaired histone H3(K9) methylation. Therefore, the key constitutive heterochromatin determinants can dynamically redistribute depending on physiological context but still maintain the essential function(s) of chromosomes. Thus, our data show that cathepsin L stabilizes epigenetic heterochromatin markers on pericentromeric heterochromatin and the Y chromosome through a novel mechanism that does not involve DNA methylation or affect heterochromatin structure and operates on both somatic and sex chromosomes.In eukaryotic cells, pericentromeric chromosomal regions do not completely decondense in the interphase and form heterochromatin, a more condensed and transcriptionally repressed type of chromatin morphologically distinct from decondensed and transcriptionally active euchromatin (17,21,55). Previous molecular and genetic studies had established a set of epigenetic mechanisms such as a special set of histone modifications also referred to as "histone code" (24) and DNA methylation (26) that demarcate silent heterochromatin and transcriptionally active euchromatin, separating one from the other. A key regulatory mechanism that controls heterochromatin formation is the positive feedback loop by which histone H3 trimethylated at lysine 9 (H3me3K9) recruits heterochromatin protein 1 (HP1) through direct interaction with the HP1 chromodomain (2, 27, 30). HP1, in turn, recruits histone H3(K9) methyltransferase Suv39h (24, 54) to methylate adjacent H3(K9). In addition to H3me3K9, other factors can contribute to the stable association of HP1 with chromatin (10, 59). The presence of HP1 at chromosomal loci is sufficient to induce chromatin condensation and gene repression (64). The highest concentration of HP1 and H3me3K9 is found at simple repeats in the vicinity of centromeric regions forming the largest blocks of heterochromatin, also known as pericentromeric constitutive heterochromatin. In addition, H3me3K9 is localized on chromatin clusters associated with certain ty...

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Section: Discussionmentioning

confidence: 99%

Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin

Bulynko

Hsing

Mason

et al. 2006

Molecular and Cellular Biology

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“…These molecules function as intracellular inhibitors of cysteine and serine proteases with distinct cross-class specificity, protecting cells from aberrant proteolysis by a general mechanism, using a C-terminal reactive site loop as bait and acting as a suicide substrate (44,45). Among these is Serpinb3a, the product of which specifically inhibits Ctsg (46,47) and which, along with Serpinb3b and Serpinb3c, forms part of the SCCA locus in mice (referred to herein as serpinb3a/b/c) (48). Using qRT-PCR, we confirmed upregulation of serpinb3a/b/c in the lungs of IFN-γ-blocked Nos2 -/-mice compared with control mice at day 28 p.i.…”

Section: Figurementioning

confidence: 99%

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Reece¹,

Loddenkemper²,

Askew³

et al. 2010

J. Clin. Invest.

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The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2 -/-mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2 -/-mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis.

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“…SCCA2 inhibits apoptosis possibly by inhibition of TNFinduced cathepsin G, as the reactive center loop sequence was shown to be essential [15]. SCCA1 and SCCA2 are highly similar to the mouse serpin SQN-5, which is a dual inhibitor of both chymotrypsin-like serine and papainlike cysteine proteases and considered to be an old serpin in the history of mammalian evolution [16].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Monoclonal Antibodies Directed against Squamous Cell Carcinoma Antigens: Report of the TD-10 Workshop

Nustad¹,

Dowell²,

Davis³

et al. 2004

Hum Hered

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Thirteen monoclonal antibodies directed against squamous cell carcinoma antigens (SCCA1 and SCCA2) were obtained from five international collaborating laboratories participating in the ISOBM TD-10 Workshop. Native and recombinant forms of SCCA were used in a wide variety of approaches to determine the reactivity and specificity of these antibodies. Based on reactivity, the antibodies could be divided into three groups: the SCCA1-reactive group containing those that reacted only with recombinant SCCA1 (rSCCA1) and native SCCA1 (nSCCA1) antigens, the SCCA2-reactive group containing those that reacted only with recombinant SCCA2 (rSCCA2), and the pan-reactive group containing those antibodies that reacted with rSCCA1, nSCCA1, and rSCCA2. Binding to radioiodinated rSCCA1 showed that all reactive antibodies were of a high affinity (K_d <2 × 10^–9 mol/l). Binding to labelled rSCCA2 demonstrated that five antibodies were of a high affinity (K_d <2 × 10^–9 mol/l). Antibody reactivity on Western blots was tested with nonreduced and reduced native and recombinant SCCA1 and SCCA2. In general, these findings showed that reduction had little effect on binding to SCCA1, but often a strong effect on the binding to SCCA2. Binding of antibodies to rSCCA1 and rSCCA2 in complexes with cathepsin L and G, respectively, was used to assist in the localization of epitope regions in enzyme-complexed SCCA. Cross-inhibition experiments showed that SCCA1-reactive antibodies represent two different epitope groups, and this is supported by their ability to make SCCA1-specific assays by combining antibodies from the two epitope groups. The SCCA2-reactive group represents two related antibodies and one unique as seen in cross-inhibition, but they do not form successful assay combinations. Classification of the pan-reactive antibodies is more difficult, as some epitope groups differ when results from rSCCA1 are compared with rSCCA2 as the target. However, two antibodies are outstanding, SCC107 and SCC113, as they are high-affinity antibodies which react equally well with free and protease complexes of SCCA1 and SCCA2. The precise location of epitopes was further studied using sequential overlapping peptides and homology modelling. The findings from this workshop strongly indicate that the recombinant antigens (rSCCA1 and rSCCA2) are very similar in epitope structure to the native counterparts in saliva, and squamous epithelium from normal and cancer tissues. Therefore, it is reasonable to conclude that the specificities found are reliable and have application for antibody measurement of all forms of squamous cell carcinoma in serum except SCCA2 in complex with its protease.

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The Serpin SQN-5 Is a Dual Mechanistic-Class Inhibitor of Serine and Cysteine Proteinases

Cited by 61 publications

References 41 publications

Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin

Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Characterization of Monoclonal Antibodies Directed against Squamous Cell Carcinoma Antigens: Report of the TD-10 Workshop

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