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Mito-TAILS analysis of EPEC infection

ABSTRACT: Mito-TAILS N-terminomics analysis of proteolytic events during EPEC infection of human epithelial cells, on whole-cell level and mitochondria.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Theo Klein

LAB HEAD: Christopher Overall

PROVIDER: PXD016994 | Pride | 2020-05-21

REPOSITORIES: Pride

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Insight into the Human Pathodegradome of the V8 protease from Staphylococcus aureus

Project description:The major human pathogen Staphylococcus aureus possesses ten extracellular proteases that are central to the virulence process. While some host targets of these and other bacterial proteases are known, a major bottleneck to the study of their function is the low-throughout nature of substrate identification. Rapid identification of proteolytic cleavage events in complex substrates has, however, been rendered possible by recent developments in the proteomics sub discipline of N-terminomics. Thus, herein we perform the first study of bacterial protease-host interactions, combining the S. aureus V8 protease and the infection relevant substrate human serum. In so doing, we identified ~90 host-protein targets of V8, including previously known and novel targets. Amongst these were complement components (C1r, C1s, C3,C4b, C4BPA, C5, C6, C8G, C9, CfB, CfH, and ficolin), iron sequestration and transport proteins (ceruloplasmin, serotransferrin, hemopexin, haptoglobin), clotting cascade proteins (plasminogen, kallikrein proteins, prothrombin, factors X and XII), and multiple host protease inhibitors (α2M and members of the ITIH and SERPIN families). N-terminomics also provided insight into the disruption of host protein function by highlighting specific target regions of host proteins, where V8 cleaved within peptidase and sushi domains of complement proteins, and, in the case of host protease inhibitors, cleavage occurred predominantly outside their protease-trapping motifs. Collectively, our data highlight the potential for further application of N-terminomics for the discovery of bacterial protease substrates in other host niches, and provides unique insight into the role of the V8 protease in S. aureus pathogenesis.

2021-03-29 | PXD014797 | Pride

TAILS analysis of viral protease 3C substrates

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Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development

Project description:Analysis of mouse Adamts6 and Adamts10 mutant embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics determination of ADAMTS6-cleaved sites, demonstrates a transcriptionally adapted system for fibrillin-2 proteolysis that contributes to postnatal fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of these defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.

2022-05-20 | PXD027096 | Pride

Degradomic identification of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) as an ADAMTS9 and ADAMTS20 substrate

Project description:ADAMTS9 and ADAMTS20 are homologous secreted proteases implicated in ECM proteolysis and ciliogenesis, but few relevant substrates of these proteases are currently known. Quantitative N-terminomics comparison of RPE-1 cells lacking ADAMTS9 with parental RPE-1 cells identified transmembrane protease MT1-MMP (MMP14) as a novel ADAMTS9 substrate. The resulting enhanced cell-surface MT1-MMP activity in the gene-edited cells contributes to their adhesion defect, but not lack of cilia. A key physiological function of ADAMTS9/20 may be to dampen cell-surface MT1-MMP activity.

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Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

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2018-01-30 | PXD006235 | Pride

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2023-04-07 | PXD040648 | Pride

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