Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity

Orlando Maiorani; Eliana Pivetta; Alessandra Capuano; Teresa Maria Elisa Modica; Bruna Wassermann; Francesco Bucciotti; Alfonso Colombatti; Roberto Doliana; Paola Spessotto

doi:10.1038/srep39974

journal article Open Access Jan 11, 2017

Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity

Orlando Maiorani Eliana Pivetta Alessandra Capuano Teresa Maria Elisa Modica Bruna Wassermann Francesco Bucciotti Alfonso Colombatti Roberto Doliana Paola Spessotto

Scientific Reports Vol. 7 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/srep39974

Abstract

AbstractThe extracellular matrix glycoprotein EMILIN1 exerts a wide range of functions mainly associated with its gC1q domain. Besides providing functional significance for adhesion and migration, the direct interaction between α4β1 integrin and EMILIN1-gC1q regulates cell proliferation, transducing net anti-proliferative effects. We have previously demonstrated that EMILIN1 degradation by neutrophil elastase (NE) is a specific mechanism leading to the loss of functions disabling its regulatory properties. In this study we further analysed the proteolytic activity of NE, MMP-3, MMP-9, and MT1-MMP on EMILIN1 and found that MMP-3 and MT1-MMP partially cleaved EMILIN1 but without affecting the functional properties associated with the gC1q domain, whereas NE was able to fully impair the interaction of gC1q with the α4β1 integrin by cleaving this domain outside of the E933 integrin binding site. By a site direct mutagenesis approach we mapped the bond between S913 and R914 residues and selected the NE-resistant R914W mutant still able to interact with the α4β1 integrin after NE treatment. Functional studies showed that NE impaired the EMILIN1-α4β1 integrin interaction by cleaving the gC1q domain in a region crucial for its proper structural conformation, paving the way to better understand NE effects on EMILIN1-cell interaction in pathological context.

Topics

No keywords indexed for this article. Browse by subject →

References

47

[1]

The Extracellular Matrix: Not Just Pretty Fibrils

Richard O. Hynes

Science 2009 10.1126/science.1176009

[2]

Watt, F. M. & Fujiwara, H. Cell-extracellular matrix interactions in normal and diseased skin. Cold Spring Harb. Perspect. Biol. 3, (2011). 10.1101/cshperspect.a005124

[3]

Streuli, C. H. Integrins and cell-fate determination. J. Cell Sci. 122, 171–177 (2009). 10.1242/jcs.018945

[4]

Moreno-Layseca, P. & Streuli, C. H. Signalling pathways linking integrins with cell cycle progression. Matrix Biol. 34, 144–153 (2014). 10.1016/j.matbio.2013.10.011

[5]

Doliana, R. et al. EMILIN, a component of the elastic fiber and a new member of the C1q/tumor necrosis factor superfamily of proteins. J. Biol. Chem. 274, 16773–16781 (1999). 10.1074/jbc.274.24.16773

[6]

Colombatti, A. et al. The EMILIN protein family. Matrix Biol. 19, 289–301 (2000). 10.1016/s0945-053x(00)00074-3

[7]

Colombatti, A. et al. The EMILIN/Multimerin family. Front Immunol. 2, 93 (2011).

[8]

Ghai, R. et al. C1q and its growing family. Immunobiology 212, 253–266 (2007). 10.1016/j.imbio.2006.11.001

[9]

Kishore, U. et al. C1q and tumor necrosis factor superfamily: modularity and versatility. Trends Immunol. 25, 551–561 (2004). 10.1016/j.it.2004.08.006

[10]

Colombatti, A., Bressan, G. M., Castellani, I. & Volpin, D. Glycoprotein 115, a glycoprotein isolated from chick blood vessels, is widely distributed in connective tissue. J. Cell Biol. 100, 18–26 (1985). 10.1083/jcb.100.1.18

[11]

Colombatti, A., Poletti, A., Bressan, G. M., Carbone, A. & Volpin, D. Widespread codistribution of glycoprotein gp 115 and elastin in chick eye and other tissues. Coll. Relat Res. 7, 259–275 (1987). 10.1016/s0174-173x(87)80032-8

[12]

Danussi, C. et al. Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. Mol. Cell Biol. 28, 4026–4039 (2008). 10.1128/mcb.02062-07

[13]

Danussi, C. et al. EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation. J. Cell Biol. 195, 131–145 (2011). 10.1083/jcb.201008013

[14]

Emilin1 Links TGF-β Maturation to Blood Pressure Homeostasis

Luca Zacchigna, Carmine Vecchione, Antonella Notte et al.

Cell 2006 10.1016/j.cell.2005.12.035

[15]

Spessotto, P. et al. beta 1 Integrin-dependent cell adhesion to EMILIN-1 is mediated by the gC1q domain. J. Biol. Chem. 278, 6160–6167 (2003). 10.1074/jbc.m208322200

[16]

Spessotto, P. et al. EMILIN1 represents a major stromal element determining human trophoblast invasion of the uterine wall. J. Cell Sci. 119, 4574–4584 (2006). 10.1242/jcs.03232

[17]

Danussi, C. et al. An EMILIN1-negative microenvironment promotes tumor cell proliferation and lymph node invasion. Cancer Prev. Res. (Phila) 5, 1131–1143 (2012). 10.1158/1940-6207.capr-12-0076-t

[18]

Verdone, G. et al. The solution structure of EMILIN1 globular C1q domain reveals a disordered insertion necessary for interaction with the alpha4beta1 integrin. J. Biol. Chem. 283, 18947–18956 (2008). 10.1074/jbc.m801085200

[19]

Rose, D. M., Alon, R. & Ginsberg, M. H. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol. Rev. 218, 126–134 (2007). 10.1111/j.1600-065x.2007.00536.x

[20]

Hauzenberger, D., Klominek, J., Bergstrom, S. E. & Sundqvist, K. G. T lymphocyte migration: the influence of interactions via adhesion molecules, the T cell receptor, and cytokines. Crit Rev. Immunol. 15, 285–316 (1995). 10.1615/critrevimmunol.v15.i3-4.60

[21]

Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006). 10.1242/jcs.03098

[22]

Humphries, M. J. The molecular basis and specificity of integrin-ligand interactions. J. Cell Sci. 97(Pt 4), 585–592 (1990). 10.1242/jcs.97.4.585

[23]

Danussi, C. et al. EMILIN1/alpha9beta1 integrin interaction is crucial in lymphatic valve formation and maintenance. Mol. Cell Biol. 33, 4381–4394 (2013). 10.1128/mcb.00872-13

[24]

Kamarajan, P., Garcia-Pardo, A., D’Silva, N. J. & Kapila, Y. L. The CS1 segment of fibronectin is involved in human OSCC pathogenesis by mediating OSCC cell spreading, migration, and invasion. BMC. Cancer 10, 330 (2010). 10.1186/1471-2407-10-330

[25]

Zucchetto, A. et al. The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells. Leukemia 26, 1301–1312 (2012). 10.1038/leu.2011.369

[26]

Lund, S. A. et al. Osteopontin mediates macrophage chemotaxis via alpha4 and alpha9 integrins and survival via the alpha4 integrin. J. Cell Biochem. 114, 1194–1202 (2013). 10.1002/jcb.24462

[27]

Pivetta, E. et al. Neutrophil elastase-dependent cleavage compromises the tumor suppressor role of EMILIN1. Matrix Biol. 34, 22–32 (2014). 10.1016/j.matbio.2014.01.018

[28]

Pivetta, E. et al. Local inhibition of elastase reduces EMILIN1 cleavage reactivating lymphatic vessel function in a mouse lymphoedema model. Clin. Sci. (Lond) 130, 1221–1236 (2016). 10.1042/cs20160064

[29]

Stegemann, C. et al. Proteomic identification of matrix metalloproteinase substrates in the human vasculature. Circ. Cardiovasc. Genet. 6, 106–117 (2013). 10.1161/circgenetics.112.964452

[30]

Mongiat, M. et al. Self-assembly and supramolecular organization of EMILIN. J. Biol. Chem. 275, 25471–25480 (2000). 10.1074/jbc.m001426200

[31]

Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites

Oliver Schilling, Christopher M Overall

Nature Biotechnology 2008 10.1038/nbt1408

[32]

Serine Protease Mechanism and Specificity

Lizbeth Hedstrom

Chemical Reviews 2002 10.1021/cr000033x

[33]

Bank, U. & Ansorge, S. More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control. J. Leukoc. Biol. 69, 197–206 (2001). 10.1189/jlb.69.2.197

[34]

Pham, C. T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006). 10.1038/nri1841

[35]

Mittendorf, E. A. et al. Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response. Cancer Res. 72, 3153–3162 (2012). 10.1158/0008-5472.can-11-4135

[36]

Houghton, A. M. et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat. Med. 16, 219–223 (2010). 10.1038/nm.2084

[37]

Gregory, A. D. et al. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. J. Leukoc. Biol. 98, 143–152 (2015). 10.1189/jlb.3hi1014-493r

[38]

Gregory, A. D., Hale, P., Perlmutter, D. H. & Houghton, A. M. Clathrin pit-mediated endocytosis of neutrophil elastase and cathepsin G by cancer cells. J. Biol. Chem. 287, 35341–35350 (2012). 10.1074/jbc.m112.385617

[39]

Wei, Z., Lei, X., Seldin, M. M. & Wong, G. W. Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity. J. Biol. Chem. 287, 35804–35814 (2012). 10.1074/jbc.m112.365965

[40]

Waki, H. et al. Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 146, 790–796 (2005). 10.1210/en.2004-1096

[41]

Yuan, Y. et al. C1q-TNF-related protein-9, a novel cardioprotetcive cardiokine, requires proteolytic cleavage to generate a biologically active globular domain isoform. Am. J. Physiol Endocrinol. Metab 308, E891–E898 (2015). 10.1152/ajpendo.00450.2014

[42]

Ruiz, S., Henschen-Edman, A. H., Nagase, H. & Tenner, A. J. Digestion of C1q collagen-like domain with MMPs-1,-2,-3, and -9 further defines the sequence involved in the stimulation of neutrophil superoxide production. J. Leukoc. Biol. 66, 416–422 (1999). 10.1002/jlb.66.3.416

[43]

Tissot, B. et al. Mass spectrometry analysis of the oligomeric C1q protein reveals the B chain as the target of trypsin cleavage and interaction with fucoidan. Biochemistry 44, 2602–2609 (2005). 10.1021/bi047802h

[44]

Casasnovas, J. M., Pieroni, C. & Springer, T. A. Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily. Proc. Natl. Acad. Sci. USA 96, 3017–3022 (1999). 10.1073/pnas.96.6.3017

[45]

Cannizzaro, R. et al. Endomicroscopy and cancer: a new approach to the visualization of neoangiogenesis. Gastroenterol. Res. Pract. 2012, 537170 (2012). 10.1155/2012/537170

[46]

Spessotto, P. et al. Fluorescence-based assays for in vitro analysis of cell adhesion and migration. Methods Mol. Biol. 522, 221–250 (2009). 10.1007/978-1-59745-413-1_16

[47]

Xing, J. Z. et al. Dynamic monitoring of cytotoxicity on microelectronic sensors. Chem. Res. Toxicol. 18, 154–161 (2005). 10.1021/tx049721s

Metrics

22

Citations

47

References

Details

Published: Jan 11, 2017
Vol/Issue: 7(1)
License: View

Authors

Teresa Maria Elisa Modica

Cite This Article

Orlando Maiorani, Eliana Pivetta, Alessandra Capuano, et al. (2017). Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity. Scientific Reports, 7(1). https://doi.org/10.1038/srep39974

Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity

You May Also Like