Quantitative Proteomics Reveals the Roles of Peroxisome-associated Proteins in Antiviral Innate Immune Responses*

Compared with whole-cell proteomic analysis, subcellular proteomic analysis is advantageous not only for the increased coverage of low abundance proteins but also for generating organelle-specific data containing information regarding dynamic protein movement. In the present study, peroxisome-enriched fractions from Sendai virus (SeV)-infected or uninfected HepG2 cells were obtained and subjected to quantitative proteomics analysis. We identified 311 proteins that were significantly changed by SeV infection. Among these altered proteins, 25 are immune response-related proteins. Further bioinformatic analysis indicated that SeV infection inhibits cell cycle-related proteins and membrane attack complex-related proteins, all of which are beneficial for the survival and replication of SeV within host cells. Using Luciferase reporter assays on several innate immune-related reporters, we performed functional analysis on 11 candidate proteins. We identified LGALS3BP and CALU as potential negative regulators of the virus-induced activation of the type I interferons.

[1]  S. Xiao,et al.  Quantitative proteomic analysis reveals that transmissible gastroenteritis virus activates the JAK-STAT1 signaling pathway. , 2014, Journal of proteome research.

[2]  M. J. Evans,et al.  HepG2 cells mount an effective antiviral interferon‐lambda based innate immune response to hepatitis C virus infection , 2014, Hepatology.

[3]  Lin Guo,et al.  RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms , 2014, PLoS pathogens.

[4]  E. Emmott,et al.  Identification of Protein Interaction Partners in Mammalian Cells Using SILAC-immunoprecipitation Quantitative Proteomics , 2014, Journal of visualized experiments : JoVE.

[5]  P. Gleeson The role of endosomes in innate and adaptive immunity. , 2014, Seminars in cell & developmental biology.

[6]  S. Bonifacino Short protocols in cell biology , 2014 .

[7]  P. Cossart,et al.  Diverse intracellular pathogens activate Type III Interferon expression from peroxisomes , 2014, Nature Immunology.

[8]  K. Bonham,et al.  Endosomes as platforms for NOD-like receptor signaling. , 2014, Cell host & microbe.

[9]  Anushya Muruganujan,et al.  Large-scale gene function analysis with the PANTHER classification system , 2013, Nature Protocols.

[10]  T. Hughes,et al.  The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation , 2013, Journal of Cell Science.

[11]  Gengfu Xiao,et al.  Identification of host proteins involved in Japanese encephalitis virus infection by quantitative proteomics analysis. , 2013, Journal of proteome research.

[12]  Jae U. Jung,et al.  The Antiviral Effector IFITM3 Disrupts Intracellular Cholesterol Homeostasis to Block Viral Entry , 2013, Cell Host & Microbe.

[13]  P. Hertzog,et al.  Mitochondrially localised MUL1 is a novel modulator of antiviral signaling , 2013, Immunology and cell biology.

[14]  J. Kagan,et al.  Signaling Organelles of the Innate Immune System , 2012, Cell.

[15]  F. Martinon The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses , 2012, Microbes and Infection.

[16]  J. Teng,et al.  The Intracellular Transport and Secretion of Calumenin-1/2 in Living Cells , 2012, PloS one.

[17]  M. Liao,et al.  Quantitative proteomics using stable isotope labeling with amino acids in cell culture reveals protein and pathway regulation in porcine circovirus type 2 infected PK-15 cells. , 2012, Journal of proteome research.

[18]  R. Ray,et al.  ISG56 and IFITM1 Proteins Inhibit Hepatitis C Virus Replication , 2011, Journal of Virology.

[19]  Gaurav D. Gaiha,et al.  IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry , 2011, PLoS pathogens.

[20]  Stanley M. Lemon,et al.  Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Initiation of Mitosis , 2011, Journal of Virology.

[21]  Lin Guo,et al.  Quantitative proteomic analysis of Salmonella enterica serovar Typhimurium under PhoP/PhoQ activation conditions. , 2011, Journal of proteome research.

[22]  F. Martinon,et al.  Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. , 2011, Current opinion in immunology.

[23]  A. Bowie,et al.  IFI16 is an innate immune sensor for intracellular DNA , 2010, Nature Immunology.

[24]  J. Whisstock,et al.  The structure and function of mammalian membrane-attack complex/perforin-like proteins. , 2010, Tissue antigens.

[25]  C. Leeuwenburgh,et al.  New insights into the role of mitochondria in aging: mitochondrial dynamics and more , 2010, Journal of Cell Science.

[26]  N. Hacohen,et al.  Peroxisomes Are Signaling Platforms for Antiviral Innate Immunity , 2010, Cell.

[27]  S. V. van IJzendoorn,et al.  The Na+/H+ Exchanger NHE6 in the Endosomal Recycling System Is Involved in the Development of Apical Bile Canalicular Surface Domains in HepG2 Cells , 2010, Molecular biology of the cell.

[28]  S. Akira,et al.  Pattern Recognition Receptors and Inflammation , 2010, Cell.

[29]  Yixue Li,et al.  Regulation of Cellular Metabolism by Protein Lysine Acetylation , 2010, Science.

[30]  T. Wakita,et al.  2',5'-Oligoadenylate synthetase-like gene highly induced by hepatitis C virus infection in human liver is inhibitory to viral replication in vitro. , 2010, Biochemical and biophysical research communications.

[31]  R. Colbert,et al.  From HLA‐B27 to spondyloarthritis: a journey through the ER , 2010, Immunological reviews.

[32]  David J. Adams,et al.  The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus , 2009, Cell.

[33]  T. Nyman,et al.  Actin and RIG-I/MAVS Signaling Components Translocate to Mitochondria upon Influenza A Virus Infection of Human Primary Macrophages1 , 2009, The Journal of Immunology.

[34]  M. Chou,et al.  The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway , 2008, Journal of Cell Science.

[35]  G. Barber,et al.  STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling , 2008, Nature.

[36]  M. Lu,et al.  TLRs antiviral effect on hepatitis B virus in HepG2 cells , 2008, Journal of applied microbiology.

[37]  Albert J R Heck,et al.  Triplex protein quantification based on stable isotope labeling by peptide dimethylation applied to cell and tissue lysates , 2008, Proteomics.

[38]  B. Williams,et al.  The p59 oligoadenylate synthetase-like protein possesses antiviral activity that requires the C-terminal ubiquitin-like domain. , 2008, The Journal of general virology.

[39]  Y. Li,et al.  The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. , 2008, Immunity.

[40]  A. Rothman,et al.  Efficient dengue virus (DENV) infection of human muscle satellite cells upregulates type I interferon response genes and differentially modulates MHC I expression on bystander and DENV-infected cells. , 2008, The Journal of general virology.

[41]  L. Maquat,et al.  NMD resulting from encephalomyocarditis virus IRES‐directed translation initiation seems to be restricted to CBP80/20‐bound mRNA , 2008, EMBO reports.

[42]  Jiyong Zhou,et al.  Proteomics Analysis of Host Cells Infected with Infectious Bursal Disease Virus*S , 2008, Molecular & Cellular Proteomics.

[43]  Seon-Yong Jeong,et al.  The role of mitochondria in apoptosis. , 2008, BMB reports.

[44]  Michael Emerman,et al.  Positive Selection and Increased Antiviral Activity Associated with the PARP-Containing Isoform of Human Zinc-Finger Antiviral Protein , 2008, PLoS genetics.

[45]  M. Knittler,et al.  Molecular Architecture of the TAP-Associated MHC Class I Peptide-Loading Complex1 , 2007, The Journal of Immunology.

[46]  Ronald J A Wanders,et al.  Biochemistry of mammalian peroxisomes revisited. , 2006, Annual review of biochemistry.

[47]  Peter K. Kim,et al.  JCB: ARTICLE The , 2022 .

[48]  M. Sheetz,et al.  The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCϵ , 2006, Journal of Cell Science.

[49]  B. He Viruses, endoplasmic reticulum stress, and interferon responses , 2006, Cell Death and Differentiation.

[50]  R. Wanders,et al.  Proteomic analysis of mouse kidney peroxisomes: identification of RP2p as a peroxisomal nudix hydrolase with acyl-CoA diphosphatase activity. , 2006, The Biochemical journal.

[51]  J. Gorvel,et al.  Pathogen–endoplasmic-reticulum interactions: in through the out door , 2006, Nature Reviews Immunology.

[52]  L. Medina-Kauwe,et al.  Intracellular trafficking of nonviral vectors , 2005, Gene Therapy.

[53]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[54]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[55]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[56]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[57]  J. Bonifacino,et al.  Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C. Marshall,et al.  Cdc42–MRCK and Rho–ROCK signalling cooperate in myosin phosphorylation and cell invasion , 2005, Nature Cell Biology.

[59]  S. Akira,et al.  Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus* , 2005, Journal of Biological Chemistry.

[60]  C. Cheng‐Mayer,et al.  Molecular Mechanism of hTid-1, the Human Homolog of Drosophila Tumor Suppressor l(2)Tid, in the Regulation of NF-κB Activity and Suppression of Tumor Growth , 2005, Molecular and Cellular Biology.

[61]  C. D. Krause,et al.  Interferons, interferon‐like cytokines, and their receptors , 2004, Immunological reviews.

[62]  R. N. Harty,et al.  Phospholipid Scramblase 1 Potentiates the Antiviral Activity of Interferon , 2004, Journal of Virology.

[63]  K. Gunter,et al.  Calcium and mitochondria , 2004, FEBS letters.

[64]  H. Ohno,et al.  Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. , 2003, Cell structure and function.

[65]  S. V. van IJzendoorn,et al.  Oncostatin M regulates membrane traffic and stimulates bile canalicular membrane biogenesis in HepG2 cells , 2002, The EMBO journal.

[66]  S. Aresta,et al.  A novel Rho GTPase-activating-protein interacts with Gem, a member of the Ras superfamily of GTPases. , 2002, The Biochemical journal.

[67]  L. Strizzi,et al.  Expression of glycoprotein 90K in human malignant pleural mesothelioma: correlation with patient survival , 2002, The Journal of pathology.

[68]  A. Marchetti,et al.  Expression of 90K (Mac-2 BP) correlates with distant metastasis and predicts survival in stage I non-small cell lung cancer patients. , 2002, Cancer research.

[69]  L. Maquat,et al.  Evidence for a Pioneer Round of mRNA Translation mRNAs Subject to Nonsense-Mediated Decay in Mammalian Cells Are Bound by CBP80 and CBP20 , 2001, Cell.

[70]  K. Griffin,et al.  Identification of Peroxisome Proliferator-responsive Human Genes by Elevated Expression of the Peroxisome Proliferator-activated Receptor α in HepG2 Cells* , 2001, The Journal of Biological Chemistry.

[71]  N. Tinari,et al.  Adhesion to 90K (Mac-2 BP) as a mechanism for lymphoma drug resistance in vivo. , 2000, Blood.

[72]  R. Lamb,et al.  The Paramyxovirus Simian Virus 5 V Protein Slows Progression of the Cell Cycle , 2000, Journal of Virology.

[73]  S. South,et al.  Pex19 Binds Multiple Peroxisomal Membrane Proteins, Is Predominantly Cytoplasmic, and Is Required for Peroxisome Membrane Synthesis , 2000, The Journal of cell biology.

[74]  T. McLean,et al.  Herpes simplex virus type 1 infection imposes a G(1)/S block in asynchronously growing cells and prevents G(1) entry in quiescent cells. , 2000, Virology.

[75]  J. Shaughnessy,et al.  Leukaemia disease genes: large-scale cloning and pathway predictions , 1999, Nature Genetics.

[76]  S. Naidu,et al.  The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27. , 1999, American journal of human genetics.

[77]  S. Reed,et al.  Cell Cycle Arrest during Measles Virus Infection: a G0-Like Block Leads to Suppression of Retinoblastoma Protein Expression , 1999, Journal of Virology.

[78]  M. Stevenson,et al.  Establishment of a Functional Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcription Complex Involves the Cytoskeleton , 1998, The Journal of experimental medicine.

[79]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[80]  T. Honjo,et al.  Calumenin, a Ca2+-binding Protein Retained in the Endoplasmic Reticulum with a Novel Carboxyl-terminal Sequence, HDEF* , 1997, The Journal of Biological Chemistry.

[81]  D. Dittmer,et al.  Human cytomegalovirus infection inhibits G1/S transition , 1997, Journal of virology.

[82]  C. Bauvy,et al.  Transfer of Free Polymannose-type Oligosaccharides from the Cytosol to Lysosomes in Cultured Human Hepatocellular Carcinoma HEPG2 Cells , 1997, The Journal of cell biology.

[83]  J. Luban,et al.  Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B , 1995, Journal of virology.

[84]  Y. Nonomura,et al.  Myosin-actin interaction plays an important role in human immunodeficiency virus type 1 release from host cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[85]  A. Ullrich,et al.  The secreted tumor-associated antigen 90K is a potent immune stimulator. , 1994, The Journal of biological chemistry.

[86]  D. Rickwood,et al.  Centrifugation: Essential Data , 1994 .

[87]  P. Sismondi,et al.  Prognostic value of a novel circulating serum 90K antigen in breast cancer. , 1994, British Journal of Cancer.

[88]  R. Wanders,et al.  Properties of the ATPase activity associated with peroxisome-enriched fractions from rat liver: comparison with mitochondrial F1F0-ATPase. , 1990, Biochimica et biophysica acta.

[89]  K. Münger,et al.  The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. , 1989, Science.

[90]  E. Harlow,et al.  Cellular targets for transformation by the adenovirus E1A proteins , 1989, Cell.

[91]  B. Jockusch,et al.  Stress fiber dynamics as probed by antibodies against myosin. , 1988, European journal of cell biology.

[92]  T. Taniguchi,et al.  Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-β gene regulatory elements , 1988, Cell.

[93]  G. Gahrton,et al.  HYPOCHOLESTEROLAEMIA IN MALIGNANCY DUE TO ELEVATED LOW-DENSITY-LIPOPROTEIN-RECEPTOR ACTIVITY IN TUMOUR CELLS: EVIDENCE FROM STUDIES IN PATIENTS WITH LEUKAEMIA , 1985, The Lancet.

[94]  T. Taniguchi,et al.  Molecular cloning of human interferon cDNA. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[95]  R. Wattiaux,et al.  Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. , 1955, The Biochemical journal.

[96]  Stephen J. Elledge,et al.  Supplemental Data The IFITM Proteins Mediate Cellular Resistance to Influenza A H 1 N 1 Virus , West Nile Virus , and Dengue Virus , 2009 .

[97]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[98]  De,et al.  Tissue Fractionation Studies , 2005 .

[99]  B. Sodeik,et al.  The role of the cytoskeleton during viral infection. , 2005, Current topics in microbiology and immunology.

[100]  A. Salonen,et al.  Viral RNA Replication in Association with Cellular Membranes , 2005, Current topics in microbiology and immunology.

[101]  J. Hiscox,et al.  The Cell Cycle and Virus Infection , 2005, Methods in molecular biology.

[102]  Zhijian J. Chen,et al.  Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. , 2005, Cell.

[103]  Z. Zhai,et al.  VISA is an adapter protein required for virus-triggered IFN-beta signaling. , 2005, Molecular cell.

[104]  J. Shabanowitz,et al.  Proteomic analysis of early melanosomes: identification of novel melanosomal proteins. , 2003, Journal of proteome research.

[105]  C. Lamers,et al.  Letter: Streptozotocin in the Zollinger-Ellison syndrome. , 1975, Lancet.