MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway.
Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.
Ha
Un-Hwan
UH
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Lim
Jae Hyang
JH
Kim
Hyun-Joong
HJ
Wu
Weihui
W
Jin
Shouguang
S
Xu
Haidong
H
Li
Jian-Dong
JD
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018928:Immunity, Mucosal; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053594:Myeloid Differentiation Factor 88; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000378:metabolism; D013301:Streptolysins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D054462:p21-Activated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D001426:Bacterial Proteins; C524678:MUC5AC protein, human; C507779:MYD88 protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D013301:Streptolysins; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C032290:plY protein, Streptococcus pneumoniae; C116367:PAK4 protein, human; C492065:Pak4 protein, mouse; D054462:p21-Activated Kinases; D048670:MAP Kinase Kinase 4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
Curr Opin Cell Biol. 1999 Apr;11(2):211-8
10209154
Infect Immun. 1992 Jan;60(1):111-6
1729176
Mol Microbiol. 1991 Aug;5(8):1883-8
1766369
J Biol Chem. 2003 Jul 25;278(30):27811-9
12734193
J Clin Invest. 2002 Mar;109(5):571-7
11877463
Am J Respir Cell Mol Biol. 2001 Nov;25(5):533-7
11713093
Trends Cell Biol. 1999 Sep;9(9):350-5
10461188
Biochem Biophys Res Commun. 2007 Aug 3;359(3):691-6
17555715
J Immunol. 2006 Feb 1;176(3):1899-907
16424221
BMC Mol Biol. 2004 May 04;5:2
15125785
Ann Otol Rhinol Laryngol. 2002 Jun;111(6):507-17
12090706
Am J Physiol Lung Cell Mol Physiol. 2001 Jan;280(1):L165-72
11133506
J Biol Chem. 2001 Oct 19;276(42):39002-11
11489891
Am J Physiol. 1999 Apr;276(4):L549-55
10198352
J Biol Chem. 1996 Nov 1;271(44):27205-8
8910287
J Biol Chem. 2004 Sep 10;279(37):39085-93
15262961
J Infect Dis. 2001 Feb 15;183(4):604-11
11170986
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2274-9
16461893
J Biol Chem. 1999 Jul 9;274(28):19949-56
10391943
Cell Signal. 2004 Jul;16(7):769-79
15115656
J Immunol. 2007 Feb 1;178(3):1736-47
17237423
Cell Physiol Biochem. 2005;15(1-4):29-40
15665513
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3081-6
10077640
Mol Cell Biol. 2000 Jan;20(2):453-61
10611223
Biochem Biophys Res Commun. 2004 Nov 19;324(3):1087-94
15485666
J Mol Biol. 2004 Nov 26;344(3):683-95
15533438
J Biol Chem. 2003 Jun 27;278(26):23243-50
12690113
J Biol Chem. 2003 Sep 19;278(38):36942-52
12855694
Cell. 1999 May 28;97(5):647-55
10367893
Curr Opin Infect Dis. 2001 Apr;14(2):173-9
11979129
Physiol Rev. 2006 Jan;86(1):245-78
16371599
J Biol Chem. 1997 Jul 4;272(27):16917-23
9202001
Microb Drug Resist. 1997 Spring;3(1):19-26
9109093
J Biol Chem. 2002 Dec 6;277(49):47444-50
12356755
Science. 1995 Nov 24;270(5240):1326-31
7481820
J Biol Chem. 2005 Dec 16;280(50):41192-200
16227624
Genes Dev. 2000 Jul 15;14(14):1729-33
10898787
Infect Immun. 1995 Feb;63(2):448-55
7822009
Infect Immun. 1989 Jul;57(7):2037-42
2731982
Int J Oncol. 2006 Jul;29(1):33-40
16773182
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1966-71
12569171
Ann Otol Rhinol Laryngol. 1988 May-Jun;97(3 Pt 1):272-4
3377394
J Biol Chem. 1998 Mar 20;273(12):6812-20
9506983
J Immunol. 2001 Nov 15;167(10):5948-54
11698473
EMBO J. 1998 Nov 16;17(22):6527-40
9822598
J Biol Chem. 2001 Apr 27;276(17):14414-9
11278822
Infect Immun. 2005 Oct;73(10):6479-87
16177320
Curr Opin Immunol. 2003 Aug;15(4):396-401
12900270