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3. Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86

Author

Liu, Haiyin, Wilson, Kayla R., Firth, Ashley M., Macri, Christophe, Schriek, Patrick, Blum, Annabelle B., Villar, Javiera, Wormald, Samuel, Shambrook, Mitch, Xu, Bangyan, Lim, Hui Jing, McWilliam, Hamish E. G., Hill, Andrew F., Edgington-Mitchell, Laura E., Caminschi, Irina, Lahoud, Mireille H., Segura, Elodie, Herold, Marco J., Villadangos, Jose A., and Mintern, Justine D.

Published
2022
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5. TLR9‐dependent dendritic cell maturation promotes IL‐6‐mediated upregulation of cathepsin X.

Author

Xu, Bangyan, Anderson, Bethany M, Mintern, Justine D, and Edgington‐Mitchell, Laura E

Subjects
DENDRITIC cells, CELLULAR control mechanisms, CATHEPSINS, IMMUNE response, PROTEOLYTIC enzymes
Abstract

Cysteine cathepsins are lysosomal proteases subject to dynamic regulation within antigen‐presenting cells during the immune response and associated diseases. To investigate the regulation of cathepsin X, a carboxy‐mono‐exopeptidase, during maturation of dendritic cells (DCs), we exposed immortalized mouse DCs to various Toll‐like receptor agonists. Using a cathepsin X‐selective activity‐based probe, sCy5‐Nle‐SY, we observed a significant increase in cathepsin X activation upon TLR‐9 agonism with CpG, and to a lesser extent with Pam3 (TLR1/2), FSL‐1 (TLR2/6) and LPS (TLR4). Despite clear maturation of DCs in response to Poly I:C (TLR3), cathepsin X activity was only slightly increased by this agonist, suggesting differential regulation of cathepsin X downstream of TLR activation. We demonstrated that cathepsin X was upregulated at the transcriptional level in response to CpG. This occurred at late time points and was not dampened by NF‐κB inhibition. Factors secreted from CpG‐treated cells were able to provoke cathepsin X upregulation when applied to naïve cells. Among these factors was IL‐6, which on its own was sufficient to induce transcriptional upregulation and activation of cathepsin X. IL‐6 is highly secreted by DCs in response to CpG but much less so in response to poly I:C, and inhibition of the IL‐6 receptor subunit glycoprotein 130 prevented CpG‐mediated cathepsin X upregulation. Collectively, these results demonstrate that cathepsin X is differentially transcribed during DC maturation in response to diverse stimuli, and that secreted IL‐6 is critical for its dynamic regulation. [ABSTRACT FROM AUTHOR]

Published
2024
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10. High-Resolution Confocal Fluorescence Imaging of Serine Hydrolase Activity in Cryosections – Application to Glioma Brain Unveils Activity Hotspots Originating from Tumor-Associated Neutrophils

Author

Aaltonen, Niina, Singha, Prosanta K., Jakupović, Hermina, Wirth, Thomas, Samaranayake, Haritha, Pasonen-Seppänen, Sanna, Rilla, Kirsi, Varjosalo, Markku, Edgington-Mitchell, Laura E., Kasperkiewicz, Paulina, Drag, Marcin, Kälvälä, Sara, Moisio, Eemeli, Savinainen, Juha R., and Laitinen, Jarmo T.

Published
2020
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18. Myoepithelial cell‐specific expression of stefin A as a suppressor of early breast cancer invasion

Author

Duivenvoorden, Hendrika M, Rautela, Jai, Edgington‐Mitchell, Laura E, Spurling, Alex, Greening, David W, Nowell, Cameron J, Molloy, Timothy J, Robbins, Elizabeth, Brockwell, Natasha K, Lee, Cheok Soon, Chen, Maoshan, Holliday, Anne, Selinger, Cristina I, Hu, Min, Britt, Kara L, Stroud, David A, Bogyo, Matthew, Möller, Andreas, Polyak, Kornelia, Sloane, Bonnie F, OʼToole, Sandra A, and Parker, Belinda S

Published
2017
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22. MHC Class II Ubiquitination Regulates Dendritic Cell Function and Immunity

Author

Wilson, Kayla R., primary, Jenika, Devi, additional, Blum, Annabelle B., additional, Macri, Christophe, additional, Xu, Bangyan, additional, Liu, Haiyin, additional, Schriek, Patrick, additional, Schienstock, Dominik, additional, Francis, Lauren, additional, Makota, F. Victor, additional, Ishido, Satoshi, additional, Mueller, Scott N., additional, Lahoud, Mireille H., additional, Caminschi, Irina, additional, Edgington-Mitchell, Laura E., additional, Villadangos, Jose A., additional, and Mintern, Justine D., additional

Published
2021
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24. Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models

Author

Tu, Nguyen Huu, primary, Inoue, Kenji, additional, Chen, Elyssa, additional, Anderson, Bethany M., additional, Sawicki, Caroline M., additional, Scheff, Nicole N., additional, Tran, Hung D., additional, Kim, Dong H., additional, Alemu, Robel G., additional, Yang, Lei, additional, Dolan, John C., additional, Liu, Cheng Z., additional, Janal, Malvin N., additional, Latorre, Rocco, additional, Jensen, Dane D., additional, Bunnett, Nigel W., additional, Edgington-Mitchell, Laura E., additional, and Schmidt, Brian L., additional

Published
2021
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27. Additional file 1 of High-Resolution Confocal Fluorescence Imaging of Serine Hydrolase Activity in Cryosections – Application to Glioma Brain Unveils Activity Hotspots Originating from Tumor-Associated Neutrophils

Author

Aaltonen, Niina, Prosanta K. Singha, Jakupović, Hermina, Wirth, Thomas, Haritha Samaranayake, Pasonen-Seppänen, Sanna, Rilla, Kirsi, Varjosalo, Markku, Edgington-Mitchell, Laura E., Kasperkiewicz, Paulina, Drag, Marcin, Kälvälä, Sara, Moisio, Eemeli, Savinainen, Juha R., and Laitinen, Jarmo T.

Abstract

Additional file 1 : Figure S1. Activity-based protein profiling (ABPP) and the power of this approach to unveil SH activity in glioma. Figure S2. Characteristics of the rat BT4C gliosarcoma model. Figure S3. Coronal plane MRI images of glioma and control brains. Figure S4. Testing various fixation method for rodent brain sections. Figure S5. Effect of TAMRA-FP concentration on fluorescence signal in mouse brain sections. Figure S6. Effects of pH and buffer composition on TAMRA-FP signal and its inhibitor sensitivity. Figure S7. Comparative gel-based ABPP of seven animals confirming distinct SH activity profiles between glioma and control brain. Figure S8. Confocal imaging of SH activity in relation to proliferating tumor cells. Figure S9. Confocal imaging of SH activity in relation to astrocytes. Figure S10. Confocal imaging of SH activity in relation to blood vessels. Figure S11. Confocal imaging of SH activity in relation to heme oxygenase 1 (HO-1). Figure S12. Confocal imaging of SH activity in relation to microglial marker Iba1. Figure S13. Confocal imaging of SH activity in relation to hyaluronan (HA). Figure S14. Confocal imaging of SH activity in relation to HA receptor CD44. Figure S15. Confocal imaging of SH activity in relation to the stiffness marker pMLC2. Figure S16. Confocal imaging of SH activity in relation to the stiffness marker tenascin C. Figure S17. Confocal imaging of SH activity in relation to CD45, a marker for nucleated hematopoietic cells. Figure S18. Confocal imaging of SH activity in relation to CD11b/c, a marker for phagocytes. Figure S19. Confocal imaging of SH activity in relation to CD68, a marker for monocytes and macrophages. Figure S20. Confocal imaging of SH activity in relation to CD163, a marker for monocytes and macrophages. Figure S21. Confocal imaging of SH activity in relation to CD169, a marker for macrophages. Figure S22. Confocal imaging of SH activity in relation to T cell marker CD4. Figure S23. Confocal imaging of SH activity in relation to T cell marker CD8. Figure S24. Confocal imaging of SH activity in relation to FcεRIγ, a marker for mast cells, eosinophils, basophils and monocytes. Figure S25. Confocal imaging of SH activity in relation to chymase (CMA1), a marker for mast cells. Figure S26. TAMRA-FP signal at the site of injection in sham-operated animals. Figure S27. Gel-ABPP of rat glioma proteomes using Cy5-labeled serine protease activity probes PK-DPP and V-DPP. Figure S28. Tissue-ABPP of glioma sections using Cy5-labeled activity probes PK-DPP and V-DPP. Figure S29. ABPP of rat neutrophil and glioma samples using Cy5-labeled neutrophil serine protease (NSP) probes in combination with TAMRA-FP. Figure S30. Inhibitor profiles of human cathepsin G (hCTSG) and the prominent 25–30 kDa SH bands in rat bone-marrow-derived mononuclear cells and neutrophils. Figure S31. High-resolution imaging of TAMRA-FP hotspots and their inhibitor sensitivity in rat spleen. Figure S32. Confocal imaging of SH activity in rat spleen sections in relation to selected immunomarkers. Figure S33. Tissue-ABPP offers sufficient sensitivity to enable imaging of TAMRA-FP fluorescence in regions of the healthy brain.

Published
2020
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30. Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2

Author

Tu, Nguyen Huu, primary, Jensen, Dane D., additional, Anderson, Bethany M., additional, Chen, Elyssa, additional, Jimenez-Vargas, Nestor N., additional, Scheff, Nicole N., additional, Inoue, Kenji, additional, Tran, Hung D., additional, Dolan, John C., additional, Meek, Tamaryn A., additional, Hollenberg, Morley D., additional, Liu, Cheng Z., additional, Vanner, Stephen J., additional, Janal, Malvin N., additional, Bunnett, Nigel W., additional, Edgington-Mitchell, Laura E., additional, and Schmidt, Brian L., additional

Published
2020
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33. Application of a Sulfoxonium Ylide Electrophile to Generate Cathepsin X-Selective Activity-Based Probes

Author

Mountford, Simon J., primary, Anderson, Bethany M., additional, Xu, Bangyan, additional, Tay, Elean S. V., additional, Szabo, Monika, additional, Hoang, My-Linh, additional, Diao, Jiayin, additional, Aurelio, Luigi, additional, Campden, Rhiannon I., additional, Lindström, Erik, additional, Sloan, Erica K., additional, Yates, Robin M., additional, Bunnett, Nigel W., additional, Thompson, Philip E., additional, and Edgington-Mitchell, Laura E., additional

Published
2020
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36. Loss of O -Linked Protein Glycosylation in Burkholderia cenocepacia Impairs Biofilm Formation and Siderophore Activity and Alters Transcriptional Regulators

Author

Oppy, Cameron C., primary, Jebeli, Leila, additional, Kuba, Miku, additional, Oates, Clare V., additional, Strugnell, Richard, additional, Edgington-Mitchell, Laura E., additional, Valvano, Miguel A., additional, Hartland, Elizabeth L., additional, Newton, Hayley J., additional, and Scott, Nichollas E., additional

Published
2019
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38. Tissue-ABPP enables high-resolution confocal fluorescence imaging of serine hydrolase activity in cryosections – Application to glioma brain unveils activity hotspots originating from tumor-associated neutrophils

Author

Aaltonen, Niina, primary, Singha, Prosanta K., additional, Jakupović, Hermina, additional, Wirth, Thomas, additional, Samaranayake, Haritha, additional, Pasonen-Seppänen, Sanna, additional, Rilla, Kirsi, additional, Varjosalo, Markku, additional, Edgington-Mitchell, Laura E., additional, Kasperkiewicz, Paulina, additional, Drag, Marcin, additional, Kälvälä, Sara, additional, Moisio, Eemeli, additional, Savinainen, Juha R., additional, and Laitinen, Jarmo T., additional

Published
2019
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39. Loss ofO-linked protein glycosylation inBurkholderia cenocepaciaimpairs biofilm formation and siderophore production via alteration of quorum sensing regulation

Author

Oppy, Cameron C., primary, Jebeli, Leila, additional, Kuba, Miku, additional, Oates, Clare V., additional, Strugnell, Richard, additional, Edgington-Mitchell, Laura E., additional, Valvano, Miguel A., additional, Hartland, Elizabeth L., additional, Newton, Hayley J., additional, and Scott, Nichollas E., additional

Published
2019
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40. N-Terminomics/TAILS Profiling of Proteases and Their Substrates in Ulcerative Colitis

Author

Gordon, Marilyn H., primary, Anowai, Anthonia, additional, Young, Daniel, additional, Das, Nabangshu, additional, Campden, Rhiannon I., additional, Sekhon, Henna, additional, Myers, Zoe, additional, Mainoli, Barbara, additional, Chopra, Sameeksha, additional, Thuy-Boun, Peter S., additional, Kizhakkedathu, Jayachandran, additional, Bindra, Gurmeet, additional, Jijon, Humberto B., additional, Heitman, Steven, additional, Yates, Robin, additional, Wolan, Dennis W., additional, Edgington-Mitchell, Laura E., additional, MacNaughton, Wallace K., additional, and Dufour, Antoine, additional

Published
2019
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42. Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2.

Author

Nguyen Huu Tu, Jensen, Dane D., Anderson, Bethany M., Chen, Elyssa, Jimenez-Vargas, Nestor N., Scheff, Nicole N., Kenji Inoue, Tran, Hung D., Dolan, John C., Meek, Tamaryn A., Hollenberg, Morley D., Liu, Cheng Z., Vanner, Stephen J., Janal, Malvin N., Bunnett, Nigel W., Edgington-Mitchell, Laura E., and Schmidt, Brian L.

Subjects
CANCER pain, ORAL cancer, ADENYLATE cyclase, PROTEIN kinases, SQUAMOUS cell carcinoma
Abstract

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons (Par2Nav1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons from WT female mice. Par2 deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR2 at Asn30↓Arg31, proximal to the canonical trypsin activation site. Lgmn activated PAR2 by biased mechanisms in HEK293 cells to induce Ca2+ mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not β-arrestin recruitment or PAR2 endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR2 by biased mechanisms that evoke cancer pain. [ABSTRACT FROM AUTHOR]

Published
2021
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44. N-Terminomics/TAILS Profiling of Macrophages after Chemical Inhibition of Legumain

Author

Anderson, Bethany M., de Almeida, Luiz G. N., Sekhon, Henna, Young, Daniel, Dufour, Antoine, and Edgington-Mitchell, Laura E.

Abstract

Legumain (asparaginyl endopeptidase) is the only protease with a preference for cleavage after asparagine residues. Increased legumain activity is a hallmark of inflammation, neurodegenerative diseases, and cancer, and legumain inhibitors have exhibited therapeutic effects in mouse models of these pathologies. Improved knowledge of its substrates and cellular functions is a requisite to further validation of legumain as a drug target. We, therefore, aimed to investigate the effects of legumain inhibition in macrophages using an unbiased and systematic approach. By shotgun proteomics, we identified 16 094 unique peptides in RAW264.7 cells. Among these, 326 unique peptides were upregulated in response to legumain inhibition, while 241 were downregulated. Many of these proteins were associated with mitochondria and metabolism, especially iron metabolism, indicating that legumain may have a previously unknown impact on related processes. Furthermore, we used N-terminomics/TAILS (terminal amine isotopic labeling of substrates) to identify potential substrates of legumain. We identified three new proteins that are cleaved after asparagine residues, which may reflect legumain-dependent cleavage. We confirmed that frataxin, a mitochondrial protein associated with the formation of iron–sulfur clusters, can be cleaved by legumain. This further asserts a potential contribution of legumain to mitochondrial function and iron metabolism. Lastly, we also identified a potential new cleavage site within legumain itself that may give rise to a 25 kDa form of legumain that has previously been observed in multiple cell and tissue types. Collectively, these data shed new light on the potential functions of legumain and will be critical for understanding its contribution to disease.

Published
2020
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46. Legumain is activated in macrophages during pancreatitis

Author

Edgington-Mitchell, Laura E., primary, Wartmann, Thomas, additional, Fleming, Alicia K., additional, Gocheva, Vasilena, additional, van der Linden, Wouter A., additional, Withana, Nimali P., additional, Verdoes, Martijn, additional, Aurelio, Luigi, additional, Edgington-Mitchell, Daniel, additional, Lieu, TinaMarie, additional, Parker, Belinda S., additional, Graham, Bim, additional, Reinheckel, Thomas, additional, Furness, John B., additional, Joyce, Johanna A., additional, Storz, Peter, additional, Halangk, Walter, additional, Bogyo, Matthew, additional, and Bunnett, Nigel W., additional

Published
2016
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50. Cathepsin S Evokes PAR 2 -Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models.

Author

Tu, Nguyen Huu, Inoue, Kenji, Chen, Elyssa, Anderson, Bethany M., Sawicki, Caroline M., Scheff, Nicole N., Tran, Hung D., Kim, Dong H., Alemu, Robel G., Yang, Lei, Dolan, John C., Liu, Cheng Z., Janal, Malvin N., Latorre, Rocco, Jensen, Dane D., Bunnett, Nigel W., Edgington-Mitchell, Laura E., and Schmidt, Brian L.

Subjects
CANCER pain, MOUTH tumors, CONFIDENCE intervals, ANIMAL experimentation, ANALGESICS, PROTEOLYTIC enzymes, GENE expression, DESCRIPTIVE statistics, CELL lines, ODDS ratio, SQUAMOUS cell carcinoma, MICE, NOCICEPTIVE pain, ALLODYNIA, HYPERALGESIA
Abstract

Simple Summary: Oral cancer is often deadly and severely painful. Because this form of cancer pain cannot be adequately treated with current medications including opiates, new treatment approaches are needed. Cathepsin S, a lysosomal cysteine protease may play a role in oral cancer pain through a protease-activated receptor-2 (PAR2)-dependent mechanism. We undertook a series of experiments to define the role of cathepsin S in oral cancer pain. We compared cathepsin S activity in human oral cancer tumors versus patient-matched normal tissue; a human oral cancer cell line versus a benign dysplastic oral keratinocyte cell line; and in an orthotopic xenograft tongue cancer mouse model versus normal controls in mice. We localized cathepsin S in macrophages and carcinoma cells in human oral cancers. The injection of cathepsin S caused nociception in a mouse model while the injection of oral cancer cells in which the gene for cathepsin S is deleted generated less nociception. Our findings will lay the foundations for clinical trials of cathepsin S inhibitors for treating oral cancer pain. Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons. [ABSTRACT FROM AUTHOR]

Published
2021
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