title: Annexin A2 and S100A10 regulate human papillomavirus type 16 entry and intracellular trafficking in human keratinocytes.
abstract: Human papillomaviruses (HPVs) cause benign and malignant tumors of the mucosal and cutaneous epithelium. The initial events regulating HPV infection impact the establishment of viral persistence, which is requisite for malignant progression of HPV-infected lesions. However, the precise mechanisms involved in HPV entry into host cells, including the cellular factors regulating virus uptake, are not clearly defined. We show that HPV16 exposure to human keratinocytes initiates epidermal growth factor receptor (EGFR)-dependent Src protein kinase activation that results in phosphorylation and extracellular translocation of annexin A2 (AnxA2). HPV16 particles interact with AnxA2 in association with S100A10 as a heterotetramer at the cell surface in a Ca(2+)-dependent manner, and the interaction appears to involve heparan-sulfonated proteoglycans. We show multiple lines of evidence that this interaction promotes virus uptake into host cells. An antibody to AnxA2 prevents HPV16 internalization, whereas an antibody to S100A10 blocks infection at a late endosomal/lysosomal site. These results suggest that AnxA2 and S100A10 have separate roles during HPV16 binding, entry, and trafficking. Our data additionally imply that AnxA2 and S100A10 may be involved in regulating the intracellular trafficking of virus particles prior to nuclear delivery of the viral genome.
authors: Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
authors: Agnieszka
authors: A
authors: Dziduszko
authors: Michelle A
authors: MA
authors: Ozbun
mesh_terms: D017306:Annexin A2 / Q000378:metabolism*; D002458:Cell Fractionation; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D052162:Human papillomavirus 16 / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000821:virology*; D008156:Luciferases; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D009418:S100 Proteins / Q000378:metabolism*; D053586:Virus Internalization; D019061:src-Family Kinases / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D008156:Luciferases; D034741:RNA, Small Interfering; D009418:S100 Proteins; D019061:src-Family Kinases; D000099248:S100 Calcium Binding Protein A10; C472822:ANXA2 protein, human
references: Cell Signal. 2009 Jun;21(6):847-58
references: 19385045
references: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20458-63
references: 19920181
references: Cancer Prev Res (Phila). 2010 Sep;3(9):1084-92
references: 20699414
references: J Virol. 2006 Mar;80(6):2694-704
references: 16501079
references: Nat Med. 2007 Jul;13(7):857-61
references: 17603495
references: J Virol. 2006 Sep;80(18):8940-50
references: 16940506
references: PLoS Pathog. 2012 Feb;8(2):e1002519
references: 22346752
references: J Virol. 2004 Jan;78(2):751-7
references: 14694107
references: Physiol Rev. 2002 Apr;82(2):331-71
references: 11917092
references: J Exp Med. 2004 Nov 15;200(10):1337-46
references: 15545357
references: J Biol Chem. 1997 Jun 13;272(24):15093-100
references: 9182528
references: J Virol. 2001 Feb;75(3):1565-70
references: 11152531
references: J Biol Chem. 2004 Apr 2;279(14):14157-64
references: 14734570
references: Mol Ther. 2005 Apr;11(4):617-26
references: 15771964
references: PLoS One. 2008 Oct 02;3(10):e3313
references: 18836553
references: Cell Mol Life Sci. 2002 Apr;59(4):608-26
references: 12022470
references: J Virol. 2011 Nov;85(22):11809-20
references: 21900167
references: J Exp Med. 1934 Nov 30;60(6):701-22
references: 19870333
references: J Cell Sci. 2004 Jul 15;117(Pt 16):3473-80
references: 15226372
references: J Virol Methods. 2008 Mar;148(1-2):34-9
references: 18061687
references: Med Res Rev. 2002 Jan;22(1):1-25
references: 11746174
references: Cell. 1999 Mar 5;96(5):677-87
references: 10089883
references: J Virol. 2003 Mar;77(6):3846-50
references: 12610160
references: FEBS J. 2009 Dec;276(24):7206-16
references: 19878308
references: Blood. 2001 Feb 1;97(3):777-84
references: 11157497
references: J Biol Chem. 1997 Feb 7;272(6):3195-9
references: 9013554
references: J Biomed Biotechnol. 2012;2012:353687
references: 23118506
references: Histochem Cell Biol. 1998 Aug;110(2):137-48
references: 9720986
references: Biochemistry. 1995 Nov 7;34(44):14527-34
references: 7578058
references: J Biol Chem. 1986 May 15;261(14):6548-55
references: 3700408
references: J Virol. 2010 Oct;84(19):9783-92
references: 20631122
references: J Biol Chem. 2004 Oct 15;279(42):43411-8
references: 15302870
references: PLoS Pathog. 2012;8(4):e1002657
references: 22536154
references: Biochemistry. 2005 Oct 25;44(42):13795-806
references: 16229469
references: Gynecol Oncol. 2010 Jun;118(1 Suppl):S12-7
references: 20494219
references: BMC Biochem. 2003 Sep 09;4:10
references: 12962548
references: Cancer Res. 1993 Dec 15;53(24):6017-21
references: 8261416
references: J Virol. 2005 Mar;79(5):2839-46
references: 15709003
references: Biochem J. 1996 Jan 1;313 ( Pt 1):51-5
references: 8546709
references: PLoS Pathog. 2009 Apr;5(4):e1000394
references: 19390604
references: PLoS Pathog. 2009 Feb;5(2):e1000318
references: 19247434
references: J Virol. 2003 Dec;77(24):13125-35
references: 14645569
references: J Invest Dermatol. 1997 Mar;108(3):307-12
references: 9036930
references: J Biol Chem. 2009 Jan 16;284(3):1604-11
references: 18990701
references: Am J Physiol Lung Cell Mol Physiol. 2007 Aug;293(2):L354-63
references: 17513451
references: J Virol. 2013 Mar;87(5):2508-17
references: 23255786
references: J Cell Biol. 1999 Aug 23;146(4):843-54
references: 10459018
references: Eur J Biochem. 1994 Nov 1;225(3):1047-53
references: 7525285
references: J Cell Biol. 1976 Oct;71(1):172-81
references: 61966
references: J Cell Biol. 2000 Sep 4;150(5):1113-24
references: 10973999
references: Cell. 1980 Oct;21(3):829-36
references: 6254669
references: J Cell Physiol. 2012 Jun;227(6):2775-87
references: 21928315
references: J Biol Chem. 2006 Oct 20;281(42):31689-95
references: 16882661
references: J Virol. 1997 Mar;71(3):2449-56
references: 9032382
references: Matrix Biol. 2011 Mar;30(2):93-9
references: 21062643
references: J Cell Biol. 1993 Dec;123(5):1119-32
references: 8245122
references: Eur J Cell Biol. 2001 Aug;80(8):499-507
references: 11561901
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9311-6
references: 15958530
references: J Biol Chem. 1999 Feb 26;274(9):5810-22
references: 10026203
references: J Mol Biol. 2001 Dec 7;314(4):751-63
references: 11733994
references: Mol Biol Cell. 1997 Mar;8(3):533-45
references: 9188103
references: J Gen Virol. 2007 Jan;88(Pt 1):19-27
references: 17170432
references: Traffic. 2004 Aug;5(8):571-6
references: 15260827
references: Exp Dermatol. 2003 Aug;12(4):453-9
references: 12930302
references: Curr Opin Cell Biol. 2003 Aug;15(4):414-22
references: 12892781
references: J Virol. 2007 Sep;81(18):9922-31
references: 17626097
references: Gynecol Oncol. 2010 May;117(2 Suppl):S5-10
references: 20304221
references: J Biol Chem. 2010 Apr 30;285(18):13569-79
references: 20181947
references: PLoS One. 2011 Apr 29;6(4):e19390
references: 21572519
references: J Virol. 2002 Nov;76(22):11291-300
references: 12388689
references: Nature. 2007 Apr 26;446(7139):1030-7
references: 17460664
references: Cell Signal. 1997 May-Jun;9(3-4):299-304
references: 9218131
references: Virology. 2003 Mar 1;307(1):1-11
references: 12667809
references: J Gen Virol. 2009 Nov;90(Pt 11):2724-2730
references: 19605586
references: Virology. 2011 Apr 25;413(1):12-8
references: 21382632
references: J Biol Chem. 1995 Jun 16;270(24):14399-404
references: 7782301
references: J Oncol. 2011;2011:509036
references: 21234307
references: Oncogene. 2003 Mar 13;22(10):1475-85
references: 12629510
references: Curr Biol. 2001 Jul 24;11(14):1136-41
references: 11509239
references: PLoS One. 2012;7(8):e43519
references: 22927980
references: Nature. 2003 Jul 24;424(6947):456-61
references: 12879076
references: Mol Biol Cell. 2012 May;23(10):1964-75
references: 22438584
references: Nat Med. 2011 May;17(5):589-95
references: 21516087
references: J Cell Sci. 1997 Jan;110 ( Pt 2):221-8
references: 9044052
references: Traffic. 2007 Aug;8(8):951-8
references: 17547702
references: Virol J. 2007 Feb 26;4:19
references: 17324266
references: J Cell Biol. 1996 Jul;134(2):559-72
references: 8707838
references: J Gen Virol. 1999 Jul;80 ( Pt 7):1807-1816
references: 10423150
references: PLoS Pathog. 2011 Oct;7(10):e1002285
references: 21998584
references: Asian J Androl. 2010 May;12(3):405-14
references: 20118949
references: Int J Cell Biol. 2012;2012:852430
references: 22505935
references: Biochim Biophys Acta. 1998 Mar 27;1402(2):115-30
references: 9561798
references: J Cell Biol. 2011 Dec 26;195(7):1071-82
references: 22123832
references: PLoS One. 2007 Oct 31;2(10):e1118
references: 17971878