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Of Myd88 Associates with TLR5 to Inhibit Recruitment Receptor In Published January 16, 2012, doi:10.4049/jimmunol.1102405 The Journal of Immunology Membrane-Tethered MUC1 Mucin Is Phosphorylated by Epidermal Growth Factor Receptor in Airway Epithelial Cells and Associates with TLR5 To Inhibit Recruitment of MyD88 Kosuke Kato,* Erik P. Lillehoj,† Yong Sung Park,* Tsuyoshi Umehara,* Nicholas E. Hoffman,‡ Muniswamy Madesh,‡ and K. Chul Kim* MUC1 is a membrane-tethered mucin glycoprotein expressed on the apical surface of mucosal epithelial cells. Previous in vivo and in vitro studies established that MUC1 counterregulates airway inflammation by suppressing TLR signaling. In this article, we elucidate the mechanism by which MUC1 inhibits TLR5 signaling. Overexpression of MUC1 in HEK293 cells dramatically reduced Pseudomonas aeruginosa-stimulated IL-8 expression and decreased the activation of NF-kB and MAPK compared with cells not expressing MUC1. However, overexpression of MUC1 in HEK293 cells did not affect NF-kB or MAPK activation in response to TNF-a. Overexpression of MyD88 abrogated the ability of MUC1 to inhibit NF-kB activation, and MUC1 over- expression inhibited flagellin-induced association of TLR5/MyD88 compared with controls. The MUC1 cytoplasmic tail associated with TLR5 in all cells tested, including HEK293T cells, human lung adenocarcinoma cell line A549 cells, and human and mouse primary airway epithelial cells. Activation of epidermal growth factor receptor tyrosine kinase with TGF-a–induced phosphor- ylation of the MUC1 cytoplasmic tail at the Y46EKV sequence and increased association of MUC1/TLR5. Finally, in vivo experi- ments demonstrated increased immunofluorescence colocalization of Muc1/TLR5 and Muc1/phosphotyrosine staining patterns in mouse airway epithelium and increased Muc1 tyrosine phosphorylation in mouse lung homogenates following P. aeruginosa infection. In conclusion, epidermal growth factor receptor tyrosine phosphorylates MUC1, leading to an increase in its association with TLR5, thereby competitively and reversibly inhibiting recruitment of MyD88 to TLR5 and downstream signaling events. This unique ability of MUC1 to control TLR5 signaling suggests its potential role in the pathogenesis of chronic inflammatory lung diseases. The Journal of Immunology, 2012, 188: 000–000. UC1 (MUC1 in humans, Muc1 in animals) is a trans- tandem repeats, whereas the C-terminal subunit consists of a membrane glycoprotein expressed on the apical sur- 58-aa EC juxtamembranous region, a transmembrane domain, M face of mucosal epithelial cells, as well as the surface and a highly conserved cytoplasmic tail (CT) containing multiple of hematopoietic cells (1). MUC1 was originally cloned in phosphorylation sites (1). The 72-aa MUC1 CT contains seven epithelial-derived human breast and pancreatic cancer cells (2, tyrosine residues whose phosphorylation status has been associ- 3), where it is uniformly expressed on the cell surface, as well as ated with intracellular signal transduction in cancer cells (5). in the cytosol and nucleus (4). The MUC1 protein consists of two In the airways, MUC1 expressed on exposed epithelia con- noncovalently associated polypeptide subunits: an N-terminal tributes to the first line of defense against inhaled pathogens; extracellular (EC) subunit and a C-terminal subunit. The MUC1 however, the physiological role of MUC1 during airway inflam- ectodomain is composed almost entirely of variable numbers of mation, particularly its CTwith multiple signaling motifs, is largely unknown. Previously, we reported that Muc1 knockout mice in- tranasally infected with P. aeruginosa displayed greater levels *Department of Physiology, Center for Inflammation, Translational and Clinical of airway inflammation compared with wild-type littermates. The Lung Research, Temple University School of Medicine, Philadelphia, PA 19140; †Department of Pediatrics, University of Maryland School of Medicine, Baltimore, anti-inflammatory effect of MUC1 was mediated through inhibi- MD 21201; and ‡Department of Biochemistry, Temple University School of Medi- tion of the proinflammatory TLR5-signaling pathway (6, 7), and cine, Philadelphia, PA 19140 P. aeruginosa upregulated MUC1 expression in airway epithelial Received for publication August 18, 2011. Accepted for publication December 14, cells (8). Therefore, it was concluded that increased MUC1/Muc1 2011. expression subsequent to production of proinflammatory media- This work was supported by U.S. Public Health Service Grants HL-47125 and HL- 81825 (to K.C.K.), AI-83463 (to E.P.L.), and HL-86699 (to M.M.). tors led to attenuation of TLR signaling via a negative-feedback mechanism (7). Address correspondence and reprint requests to Prof. K. Chul Kim, Department of Physiology, Temple University School of Medicine, 3420 N. Broad Street, MRB-410, TLRs comprise 10-member (human) or 12-member (mouse) Philadelphia, PA 19140. E-mail address: [email protected] families of innate immune receptors that initiate intracellular Abbreviations used in this article: CT, cytoplasmic tail; EGFR, epidermal growth signaling following ligation of pathogen-associated molecular factor receptor; IP, immunoprecipitation; MEF, mouse embryonic fibroblast; MTSE, primary mouse tracheal surface epithelial; MUC1 DCT, deletion of the MUC1 cyto- patterns (9). With the exception of TLR3, all TLRs initiate sig- plasmic tail domain; NHBE, normal human bronchial/tracheal epithelial; PAK, Pseu- naling by recruitment of the MyD88 adaptor protein that bridges domonas aeruginosa strain K; TAK1, TGF-b–activated kinase 1; TIR, Toll/IL-1R; the intracellular region of TLRs with downstream effector mole- TRAF6, TNFR-associated factor 6. cules, such as IRAK1, a serine/threonine kinase, and TNFR-asso- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 ciated factor 6 (TRAF6), an E3 ubiquitin ligase, to activate the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102405 2 MECHANISM OF CROSS-TALK BETWEEN MUC1 AND TLR5 NF-kB and MAPK pathways, resulting in the release of proin- bacteria at 60˚C for 30 min and stored at 280˚C. Pervanadate, a general flammatory cytokines and chemokines. protein tyrosine phosphatase inhibitor, was freshly prepared immediately 3 In addition to NF-kB and MAPKs, TLR5 activates the PI3K before its use as a 100 stock solution by mixing 600 mMH2O2 and 0.2 mMNaVO (11). pathway, a known mechanism for negative regulation of TLR5 3 4 signaling (10). The MUC1 CT contains a consensus binding site Cells for PI3K (5, 11), leading to the suggestion that PI3K may be re- Mouse embryonic fibroblast (MEF) cells were obtained from embryonic sponsible for MUC1-induced suppression of TLR5 signaling. day 13 embryos and maintained in DMEM supplemented with 10% FBS However, our previous study demonstrated that although MUC1 (13). Primary mouse tracheal surface epithelial (MTSE) cells were pre- activated the PI3K pathway in response to flagellin, a TLR5 ago- pared from 8–12-wk-old C57BL/6 mice and cultured as described (6). nist, PI3K was not responsible for MUC1-induced suppression Normal human bronchial/tracheal epithelial (NHBE) cells were obtained of TLR5 signaling (12). In this study, evidence is presented that from Lonza Walkersville (Walkersville, MD) and cultured at an air/liquid interface, according to the manufacturer’s protocol. A549 cells (CCL-185), MUC1 expression disrupts TLR5–MyD88 interaction and down- a human lung epithelial cell line, as well as HEK293 cells (CRL-1573) stream proinflammatory signaling and that epidermal growth factor and HEK293T cells (CRL-11268), human embryonic kidney cell lines, receptor (EGFR) activation promotes this anti-inflammatory effect were purchased from American Tissue Culture Collection (Manassas, VA). of MUC1 through tyrosine phosphorylation of the MUC1 CT. A549 cells were cultured in Opti-MEM medium supplemented with 5% FBS and antibiotics. HEK293 cells were stably transfected with the pcDNA3.1 empty vector (HEK293-pcDNA3.1 cells) or with a MUC1 Materials and Methods cDNA cloned in pcDNA3.1 using Lipofectamine 2000 (Invitrogen, Reagents Carlsbad, CA). HEK293T cells were used for transient transfection. Both types of cells were subsequently transfected with FLAG-tagged human All reagents were purchased from Sigma (St. Louis, MO), unless otherwise TLR5 cloned into the HindIII and AgeI sites of the pDsRed-Monomer- stated. The sources of the Abs and reagents were phospho-p38 (Thr180/ Hyg-N1 vector (Clontech Laboratories, Palo Alto, CA). Stable clones were Tyr182) (3D7) rabbit monoclonal, phospho-p44/42 (Thr202/Tyr204) rab- isolated in the presence of hygromycin (100 mg/ml) and referred to as bit monoclonal, phosphotyrosine (P-Tyr-100) mouse monoclonal, EGFR HEK293-TLR5 and HEK293-TLR5/MUC1 cells, respectively; they were rabbit monoclonal, AG1478 (Cell Signaling Technology, Beverly, MA), cultured in DMEM containing penicillin (100 U/ml), streptomycin (100 MyD88 (HFL296) rabbit polyclonal, MUC1 ectodomain (GP1.4) mouse mg/ml), hygromycin (100 mg/ml), and 10% FBS. monoclonal, normal rabbit IgG, normal mouse IgG (Santa Cruz Biotech- nology, Santa Cruz, CA), TLR5 (IMG-664A) mouse monoclonal (Imgenex, Western blot and immunoprecipitation analyses San Diego, CA), HRP-conjugated goat anti-mouse IgG and anti-rabbit IgG secondary Abs (KPL, Gaithersburg, MD), P. aeruginosa strain K (PAK) Western blot analysis was performed as described (12). For direct immu- flagellin rabbit antiserum (Dr. Dan Wozniak, Wake Forest University, noprecipitation (IP) analysis, the cells were extracted with lysis buffer (0.5 Winston-Salem, NC), MUC1-pcDNA3.1
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