The Interferon-Inducible Proteoglycan Testican-2/SPOCK2 Functions as a Protective Barrier against Virus Infection of Lung Epithelial Cells.

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE

Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.

Alveolar Epithelial Cells/*metabolism ; Alveolar Epithelial Cells/*virology ; Disease Resistance/*genetics ; Host-Pathogen Interactions/*genetics ; Proteoglycans/*genetics ; Virus Diseases/*etiology ; Virus Diseases/*metabolism; Animals ; Antiviral Agents/pharmacology ; Cell Line ; Disease Models, Animal ; Female ; Gene Expression ; Heparan Sulfate Proteoglycans ; Humans ; Influenza A virus/drug effects ; Mice ; Proteoglycans/metabolism ; Proteoglycans/pharmacology ; Recombinant Proteins/pharmacology ; Virus Attachment/drug effects ; Virus Replication/drug effects

Proteoglycans function not only as structural components of the extracellular compartment but also as regulators of various cellular events, including cell migration, inflammation, and infection. Many microbial pathogens utilize proteoglycans to facilitate adhesion and invasion into host cells. Here we report a secreted form of a novel heparan sulfate proteoglycan that functions against virus infection. The expression of SPOCK2/testican-2 was significantly induced in virus-infected lungs or in interferon (IFN)-treated alveolar lung epithelial cells. Overexpression from a SPOCK2 expression plasmid alone or the treatment of cells with recombinant SPOCK2 protein efficiently blocked influenza virus infection at the step of viral attachment to the host cell and entry. Moreover, mice treated with purified SPOCK2 were protected against virus infection. Sialylated glycans and heparan sulfate chains covalently attached to the SPOCK2 core protein were critical for its antiviral activity. Neuraminidase (NA) of influenza virus cleaves the sialylated moiety of SPOCK2, thereby blocking its binding to the virus. Our data suggest that IFN-induced SPOCK2 functions as a decoy receptor to bind and block influenza virus infection, thereby restricting entry of the infecting virus into neighboring cells. IMPORTANCE Here we report a novel proteoglycan protein, testican-2/SPOCK2, that prevents influenza virus infection. Testican-2/SPOCK2 is a complex type of secreted proteoglycan with heparan sulfate GAG chains attached to the core protein. SPOCK2 expression is induced upon virus infection or by interferons, and the protein is secreted to an extracellular compartment, where it acts directly to block virus-cell attachment and entry. Treatment with purified testican-2/SPOCK2 protein can efficiently block influenza virus infection in vitro and in vivo We also identified the heparan sulfate moiety as a key regulatory module for this inhibitory effect. Based on its mode of action (cell attachment/entry blocker) and site of action (extracellular compartment), we propose testican-2/SPOCK2 as a potential antiviral agent that can efficiently control influenza virus infection.
(Copyright © 2019 American Society for Microbiology.)

Curr Opin Virol. 2011 Dec;1(6):519-25. (PMID: 22328912)
J Virol. 2007 Mar;81(5):2221-30. (PMID: 17166899)
Am J Respir Crit Care Med. 2016 Aug 1;194(3):333-44. (PMID: 26959387)
J Virol. 1998 Sep;72(9):7367-73. (PMID: 9696833)
Med Res Rev. 2002 Jan;22(1):1-25. (PMID: 11746174)
J Neurochem. 1999 Jul;73(1):12-20. (PMID: 10386950)
Annu Rev Cell Biol. 1988;4:229-55. (PMID: 3143379)
Anat Rec (Hoboken). 2010 Jun;293(6):968-81. (PMID: 20503391)
Eur Rev Med Pharmacol Sci. 2018 Feb;22(3):637-644. (PMID: 29461591)
Arch Virol. 1984;81(1-2):163-70. (PMID: 6743023)
Nat Rev Microbiol. 2014 Nov;12(11):739-49. (PMID: 25263223)
Biol Chem. 2005 Jan;386(1):75-83. (PMID: 15843150)
Front Biosci (Landmark Ed). 2016 Jun 01;21:1260-77. (PMID: 27100505)
J Biol Chem. 2009 Feb 6;284(6):3768-76. (PMID: 19073595)
Am J Respir Crit Care Med. 2011 Nov 15;184(10):1164-70. (PMID: 21836138)
J Mol Biol. 1998 Sep 25;282(3):585-99. (PMID: 9737924)
Dev Neurosci. 2014;36(5):381-95. (PMID: 25138526)
EMBO Rep. 2000 Sep;1(3):282-6. (PMID: 11256613)
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):668-73. (PMID: 10639137)
Cell. 2015 Feb 12;160(4):631-643. (PMID: 25679759)
J Virol Antivir Res. 2018;2018:1-20. (PMID: 29349092)
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2241-6. (PMID: 26858407)
J Virol. 1989 Jan;63(1):52-8. (PMID: 2535752)
PLoS One. 2016 Oct 7;11(10):e0164501. (PMID: 27716790)
J Virol. 2011 Aug;85(16):8133-40. (PMID: 21680506)
Mol Cell Biol. 2009 Sep;29(17):4778-87. (PMID: 19564411)
Virology. 2002 Jun 20;298(1):73-83. (PMID: 12093175)
Cancer Res. 2003 Jun 15;63(12):3364-9. (PMID: 12810672)
Matrix Biol. 2003 May;22(3):259-66. (PMID: 12853036)
J Biol Chem. 2005 Mar 25;280(12):11274-80. (PMID: 15657052)
Toxicol Lett. 2012 Mar 25;209(3):270-6. (PMID: 22237054)
FEBS Lett. 1997 Mar 10;404(2-3):197-202. (PMID: 9119063)
Immunity. 2006 Sep;25(3):373-81. (PMID: 16979569)
Cell. 2009 Dec 24;139(7):1243-54. (PMID: 20064371)
Nucleic Acids Res. 2004 Jan 29;32(2):643-52. (PMID: 14752052)
Matrix Biol. 2015 Mar;42:11-55. (PMID: 25701227)
Biochem Biophys Res Commun. 2013 Nov 1;440(4):792-7. (PMID: 24134845)
PLoS One. 2014 Apr 01;9(4):e93413. (PMID: 24690998)
Nat Rev Immunol. 2013 Jan;13(1):46-57. (PMID: 23237964)
J Clin Invest. 2017 Jun 1;127(6):2277-2294. (PMID: 28463226)
Nat Commun. 2013;4:2763. (PMID: 24434940)
Annu Rev Immunol. 2014;32:513-45. (PMID: 24555472)
J Biol Chem. 2007 Nov 9;282(45):32802-10. (PMID: 17761672)

Keywords: SPOCK2; antiviral; extracellular matrix; influenza; proteoglycan

0 (Antiviral Agents)
0 (Heparan Sulfate Proteoglycans)
0 (Proteoglycans)
0 (Recombinant Proteins)
0 (SPOCK2 protein, human)

Date Created: 20190726 Date Completed: 20200608 Latest Revision: 20200608

20231215

PMC6798107

10.1128/JVI.00662-19

31341044