Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation
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Shigella is unique among enteric pathogens, as it invades colonic epithelia through the basolateral pole. Therefore, it has evolved the ability to breach the intestinal epithelial barrier to deploy an arsenal of effector proteins, which permits bacterial invasion and leads to a severe inflammatory response. However, the mechanisms used by Shigella to regulate epithelial barrier permeability remain unknown. To address this question, we used both an intestinal polarized model and a human ex-vivo model to further characterize the early events of host-bacteria interactions. Our results showed that secreted Serine Protease A (SepA), which belongs to the serine protease autotransporter of Enterobacteriaceae family, is responsible for critically disrupting the intestinal epithelial barrier. Such disruption facilitates bacterial transit to the basolateral pole of the epithelium, ultimately fostering the hallmarks of the disease pathology. SepA was found to cause a decrease in active LIM Kinase 1 (LIMK1) levels, a negative inhibitor of actin-remodeling proteins, namely cofilin. Correspondingly, we observed increased activation of cofilin, a major actin-polymerization factor known to control opening of tight junctions at the epithelial barrier. Furthermore, we resolved the crystal structure of SepA to elucidate its role on actin-dynamics and barrier disruption. The serine protease activity of SepA was found to be required for the regulatory effects on LIMK1 and cofilin, resulting in the disruption of the epithelial barrier during infection. Altogether, we demonstrate that SepA is indispensable for barrier disruption, ultimately facilitating Shigella transit to the basolateral pole where it effectively invades the epithelium.
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Class-2 SepA produced by Shigella flexneri and EAEC is indispensable for barrier disruption.
“Class-2 SepA produced by Shigella flexneri and EAEC is also indispensable for barrier disruption. 72”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [72]
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<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Overview of the <i>CCP</i> 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353 · see citing works
Dali server: conservation mapping in 3D
Holm, L., & Rosenstr�m, P. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq366 · Cited by 3,640 · see citing works
Signaling from Rho to the Actin Cytoskeleton Through Protein Kinases ROCK and LIM-kinase
Maekawa, M., Ishizaki, T., Boku, S., Watanabe, N., Fujita, A., Iwamatsu, A., Obinata, T., Ohashi, K., Mizuno, K., & Narumiya, S. (1999) · Science · doi:10.1126/science.285.5429.895 · Cited by 1,640 · see citing works
Maximum-likelihood density modification
Terwilliger, T. C. (2000) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444900005072 · Cited by 1,637 · see citing works
Solving structures of protein complexes by molecular replacement with Phaser
McCoy, A. J. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906045975 · Cited by 1,605 · see citing works
Terwilliger, T. C., Grosse-Kunstleve, R. W., Afonine, P. V., Moriarty, N. W., Zwart, P. H., Hung, L.-W., Read, R. J., & Adams, P. D. (2008) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s090744490705024x · Cited by 1,462 · see citing works
Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase
Arber, S., Barbayannis, F. A., Hanser, H., Schneider, C., Stanyon, C. A., Bernard, O., & Caroni, P. (1998) · Nature · doi:10.1038/31729 · Cited by 1,426 · see citing works
Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization
Yang, N., Higuchi, O., Ohashi, K., Nagata, K., Wada, A., Kangawa, K., Nishida, E., & Mizuno, K. (1998) · Nature · doi:10.1038/31735 · Cited by 1,296 · see citing works
Involvement of a plasmid in the invasive ability of Shigella flexneri
Sansonetti, P. J., Kopecko, D. J., & Formal, S. B. (1982) · Infection and Immunity · doi:10.1128/iai.35.3.852-860.1982 · Cited by 742 · see citing works
Andrianantoandro, E., & Pollard, T. D. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.08.006 · Cited by 710 · see citing works
Niwa, R., Nagata-Ohashi, K., Takeichi, M., Mizuno, K., & Uemura, T. (2002) · Cell · doi:10.1016/s0092-8674(01)00638-9 · Cited by 694 · see citing works
REGULATION OF THE MOVEMENT OF SOLUTES ACROSS TIGHT JUNCTIONS
Madara, J. (1998) · Annual Review of Physiology · doi:10.1146/annurev.physiol.60.1.143 · Cited by 522 · see citing works
McCormick, B. A., Colgan, S. P., Delp-Archer, C., Miller, S. I., & Madara, J. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.123.4.895 · Cited by 447 · see citing works
Self-citationSignaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation
Mizuno, K. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2012.11.001 · Cited by 396 · see citing works
Buchrieser, C., Glaser, P., Rusniok, C., Nedjari, H., D'Hauteville, H., Kunst, F., Sansonetti, P. J., & Parsot, C. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.02179.x · Cited by 378 · see citing works
Kotloff, K. L., Blackwelder, W. C., Nasrin, D., Nataro, J. P., Farag, T. H., van Eijk, A. M., Adegbola, R. A., Alonso, P. L., Breiman, R. F., Faruque, A. S. G., et al. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cis753 · Cited by 373 · see citing works
Henderson, I. R., Czeczulin, J., Eslava, C., Noriega, F., & Nataro, J. P. (1999) · Infection and Immunity · doi:10.1128/iai.67.11.5587-5596.1999 · Cited by 357 · see citing works
Cofilin phosphatases and regulation of actin dynamics
Huang, T. Y., DerMardirossian, C. M., & Bokoch, G. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.11.005 · Cited by 339 · see citing works
Shigella flexneri enters human colonic Caco-2 epithelial cells through the basolateral pole
Mounier, J., Vasselon, T., Hellio, R., Lesourd, M., & Sansonetti, P. J. (1992) · Infection and Immunity · doi:10.1128/iai.60.1.237-248.1992 · Cited by 318 · see citing works
Actin Depolymerization Disrupts Tight Junctions via Caveolae-mediated Endocytosis
Shen, L., & Turner, J. R. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-12-1089 · Cited by 302 · see citing works
Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis.
Perdomo, O. J., Cavaillon, J., Huerre, M., et al. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.4.1307 · Cited by 292 · see citing works
The MORPHEUS protein crystallization screen
Gorrec, F. (2009) · Journal of Applied Crystallography · doi:10.1107/s0021889809042022 · Cited by 282 · see citing works
Joint X-ray and neutron refinement withphenix.refine
Afonine, P. V., Mustyakimov, M., Grosse‐Kunstleve, R. W., Moriarty, N. W., Langan, P. A., & Adams, P. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910026582 · Cited by 280 · see citing works
Nishita, M., Tomizawa, C., Yamamoto, M., Horita, Y., Ohashi, K., & Mizuno, K. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200504029 · Cited by 220 · see citing works
Sansonetti, P. J., Arondel, J., Huerre, M., Harada, A., & Matsushima, K. (1999) · Infection and Immunity · doi:10.1128/iai.67.3.1471-1480.1999 · Cited by 216 · see citing works
Perdomo, J. J., Gounon, P., & Sansonetti, P. J. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117015 · Cited by 210 · see citing works
Improvement of molecular-replacement models withSculptor
Bunkòczi, G., & Read, R. J. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910051218 · Cited by 210 · see citing works
Ivanov, A. I., McCall, I. C., Parkos, C. A., & Nusrat, A. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-02-0163 · Cited by 206 · see citing works
Parsot, C., Ménard, R., Gounon, P., et al. (1995) · Molecular Microbiology · doi:10.1111/j.1365-2958.1995.tb02301.x · Cited by 204 · see citing works
Genomic Characterization of Enteroaggregative Escherichia coli From Children in Mali
Boisen, N., Scheutz, F., Rasko, D. A., Redman, J. C., Persson, S., Simon, J. K., Kotloff, K. L., Levine, M. M., Sow, S. O., Tamboura, B., et al. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir757 · Cited by 189 · see citing works
Benjelloun‐Touimi, Z., Sansonetti, P. J., & Parsot, C. (1995) · Molecular Microbiology · doi:10.1111/j.1365-2958.1995.mmi_17010123.x · Cited by 189 · see citing works
Otto, B. R., Sijbrandi, R., Luirink, J., Oudega, B., Heddle, J. G., Mizutani, K., Park, S., & Tame, J. R. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412885200 · Cited by 180 · see citing works
Foulke-Abel, J., In, J., Kovbasnjuk, O., Zachos, N. C., Ettayebi, K., Blutt, S. E., Hyser, J. M., Zeng, X.-L., Crawford, S. E., Broughman, J. R., et al. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214529398 · Cited by 179 · see citing works
Harrington, S. M., Sheikh, J., Henderson, I. R., Ruiz-Perez, F., Cohen, P. S., & Nataro, J. P. (2009) · Infection and Immunity · doi:10.1128/iai.01494-08 · Cited by 156 · see citing works
Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells
Sakaguchi, T., Köhler, H., Gu, X., McCormick, B. A., & Reinecker, H. (2002) · Cellular Microbiology · doi:10.1046/j.1462-5822.2002.00197.x · Cited by 142 · see citing works
Self-citationSasakawa, C., Komatsu, K., Tobe, T., et al. (1993) · Journal of Bacteriology · doi:10.1128/jb.175.8.2334-2346.1993 · Cited by 136 · see citing works
Junker, M., Besingi, R. N., & Clark, P. L. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06607.x · Cited by 135 · see citing works
A common cofilin activity cycle in invasive tumor cells and inflammatory cells
van Rheenen, J., Condeelis, J. S., & Glogauer, M. (2009) · Journal of Cell Science · doi:10.1242/jcs.031146 · Cited by 118 · see citing works
Serine Protease Autotransporters of Enterobacteriaceae (SPATEs): Biogenesis and Function
Dautin, N. (2010) · Toxins · doi:10.3390/toxins2061179 · Cited by 113 · see citing works
Madara, J., Colgan, S. P., Nusrat, A., Delp, C., & Parkos, C. A. (1992) · Methods in Cell Science · doi:10.1007/bf01409013 · Cited by 108 · see citing works
Ruı́z-Pérez, F., Wahid, R., Faherty, C. S., Kolappaswamy, K., Rodriguez, L., Santiago, A. E., Murphy, E., Cross, A. S., Sztein, M. B., & Nataro, J. P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101006108 · Cited by 107 · see citing works
PicU, a second serine protease autotransporter of uropathogenic Escherichia coli
Parham, N. J., Srinivasan, U., Desvaux, M., Foxman, B., Marrs, C. F., & Henderson, I. R. (2003) · FEMS Microbiology Letters · doi:10.1016/s0378-1097(03)00862-0 · Cited by 97 · see citing works
Orth‐Höller, D., Ehrlenbach, S., Brockmeyer, J., Khan, A. B., Huber, G. C., Karch, H., Sarg, B., Lindner, H. H., & Würzner, R. (2010) · Infection and Immunity · doi:10.1128/iai.00488-10 · Cited by 81 · see citing works
Caspase‐mediated cleavage and activation of LIM‐kinase 1 and its role in apoptotic membrane blebbing
Tomiyoshi, G., Horita, Y., Nishita, M., et al. (2004) · Genes to Cells · doi:10.1111/j.1356-9597.2004.00745.x · Cited by 75 · see citing works
Köhler, H., Rodrigues, S., & McCormick, B. A. (2002) · Infection and Immunity · doi:10.1128/iai.70.3.1150-1158.2002 · Cited by 74 · see citing works
Self-citationZhang, L., Luo, J., Wan, P., et al. (2011) · Development · doi:10.1242/dev.046870 · Cited by 66 · see citing works
Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets
Pandey, D. B., Goyal, P., Bamburg, J. R., et al. (2005) · Blood · doi:10.1182/blood-2004-11-4377 · Cited by 63 · see citing works
McCormick, B. A., Fernandez, M. I., Siber, A. M., et al. (1999) · Cellular Microbiology · doi:10.1046/j.1462-5822.1999.00014.x · Cited by 63 · see citing works
Self-citationBenjelloun‐Touimi, Z., Si‐Tahar, M., Montecucco, C., et al. (1998) · Microbiology · doi:10.1099/00221287-144-7-1815 · Cited by 62 · see citing works
Cofilin mediates tight-junction opening by redistributing actin and tight-junction proteins
Nagumo, Y., Han, J., Bellila, A., Isoda, H., & Tanaka, T. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.10.071 · Cited by 62 · see citing works
Inactivation of brain Cofilin-1 by age, Alzheimer's disease and γ-secretase
Barone, E., Mosser, S., & Fraering, P. C. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.10.004 · Cited by 61 · see citing works
McCormick, B. A., Siber, A. M., & Maurelli, A. T. (1998) · Infection and Immunity · doi:10.1128/iai.66.9.4237-4243.1998 · Cited by 58 · see citing works
Self-citationShiobara, T., Usui, T., Han, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079954 · Cited by 58 · see citing works
Pieper, R., Fisher, C. R., Suh, M., Huang, S.-T., Parmar, P. P., & Payne, S. M. (2013) · Infection and Immunity · doi:10.1128/iai.00975-13 · Cited by 52 · see citing works
Vingadassalom, D., Campellone, K. G., Brady, M. J., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001056 · Cited by 50 · see citing works
Renn, J. P., Junker, M., Besingi, R. N., Braselmann, E., & Clark, P. L. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.11.009 · Cited by 48 · see citing works
Role of LIM Kinases in Normal and Psoriatic Human Epidermis
Honma, M., Benitah, S. A., & Watt, F. M. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-12-1173 · Cited by 48 · see citing works
Actin-based confinement of calcium responses during Shigella invasion
Nhieu, G. T. V., Liu, B. K., Zhang, J., et al. (2013) · Nature Communications · doi:10.1038/ncomms2561 · Cited by 45 · see citing works
Wang, D., Naydenov, N. G., Feygin, A., Baranwal, S., Kuemmerle, J. F., & Ivanov, A. I. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.11.023 · Cited by 44 · see citing works
Sansonetti, P. J. (1998) · Folia Microbiologica · doi:10.1007/bf02818608 · Cited by 43 · see citing works
Coron, E., Flamant, M., Aubert, P., Wedel, T., Pédron, T., Letessier, E., Galmiche, J. P., Sansonetti, P. J., & Neunlist, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004713 · Cited by 39 · see citing works
Birtley, J. R., & Curry, S. (2005) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444905007924 · Cited by 39 · see citing works
Self-citationCoagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation
Borensztajn, K., Peppelenbosch, M. P., & Spek, C. A. (2010) · Thrombosis Research · doi:10.1016/j.thromres.2010.02.018 · Cited by 34 · see citing works
Broad Spectrum Activity of a Lectin-Like Bacterial Serine Protease Family on Human Leukocytes
Ayala-Luján, J. L., Vijayakumar, V., Gong, M., Smith, R., Santiago, A. E., & Ruı́z-Pérez, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107920 · Cited by 26 · see citing works
Leonard, A., Marando, C. M., Rahman, A., & Fazal, F. (2013) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00071.2013 · Cited by 24 · see citing works
Role of Class 1 Serine Protease Autotransporter in the Pathogenesis of Citrobacter rodentium Colitis
Vijayakumar, V., Santiago, A. E., Smith, R. M., Smith, M., Robins-Browne, R. M., Nataro, J. P., & Ruı́z-Pérez, F. (2014) · Infection and Immunity · doi:10.1128/iai.01518-13 · Cited by 18 · see citing works
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Research works printed but not linked: 1
- Bowen A. Chapter 3: Infectious Diseases Related to Travel. CDC; 2016 [updated Retrieved 22 June 2016.
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- Authors
- Maldonado-Contreras, A., Birtley, J. R., Boll, E., Zhao, Y., Mumy, K. L., Toscano, J., Ayehunie, S., Reinecker, H.-C., Stern, L. J., & McCormick, B. A.
- Affiliations
- Department of Microbiology and Physiological Systems, University of Massachusetts, Medical School
- University of Massachusetts Chan Medical School (US)
- Statens Serum Institut (DK)
- Harvard University (US)
- Wright-Patterson Air Force Base (US)
- MatTek Corporation (United States) (US)
- Corresponding author
- McCormick, Beth A.
- ORCID
- Venue
- Gut Microbes
- Publisher
- Informa UK Limited
- Published
- 2017-06-28
- Volume
- 8
- Issue
- 6
- Pages
- 544-560
- ISSN
- 1949-0976 (ISSN-L)
- 1949-0984
- PMC
- PMC5730386
- OpenAlex
- W2624129866
- Cited by
- 57
- References
- 68
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 4
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Gut Microbes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (AC02‐06CH11357, 06CH11357, DE-AC02-)
- Eli Lilly and Company
- University of Massachusetts
- Charles A. King Trust
- National Institutes of Health (DE-AC02–06CH11357, DK33506, DK 043351)
- Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
- University of Massachusetts Medical School
- National Institute of Allergy and Infectious Diseases (R37AI038996, R01AI081807, R01AI113333)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056754, R01DK091247, R01DK068181, P30DK043351)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Keywords
- Shigella, SEPA, intestinal epithelial barrier, LIM kinase 1, actin cytoskeleton remodeling, tight junctions, serine protease activity, crystal structure, host-pathogen interaction, Shigella flexneri
- MeSH terms
- Bacterial Proteins, Humans, Intestinal Mucosa, Models, Biological, Mutation, Permeability, Phosphorylation, Shigella flexneri, Structure-Activity Relationship, Protein Structure, Secondary, Tight Junctions, Neutrophil Infiltration, Cell Line, Tumor, Actin Depolymerizing Factors, Host-Pathogen Interactions
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