Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling

Autoři: Fanhua Wei aff001;  Zhimin Jiang aff001;  Honglei Sun aff001;  Juan Pu aff001;  Yipeng Sun aff001;  Mingyang Wang aff001;  Qi Tong aff001;  Yuhai Bi aff003;  Xiaojing Ma aff004;  George Fu Gao aff003;  Jinhua Liu aff001
Působiště autorů: Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China aff001;  College of Agriculture, Ningxia University, Yinchuan, China aff002;  CAS Key Laboratory of Pathogenic Microbiology and Immunology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Institute of Microbiology, Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Scien aff003;  State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China aff004;  Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America aff005
Vyšlo v časopise: Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLoS Pathog 15(10): e1008062. doi:10.1371/journal.ppat.1008062
Kategorie: Research Article


Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity.

Klíčová slova:

Antibodies – Influenza – Influenza viruses – Macrophages – Small interfering RNAs – Transfection – Ubiquitination – H5N1


1. Kilbourne ED. Influenza pandemics of the 20th century. Emerg Infect Dis. 2006;12(1):9–14. doi: 10.3201/eid1201.051254 16494710

2. Petrie JG, Lauring AS. Influenza A (H7N9) virus evolution: Which genetic mutations are antigenically important? J Infect Dis. 2018.

3. Pu J, Wang S, Yin Y, Zhang G, Carter RA, Wang J, et al. Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus. Proc Natl Acad Sci U S A. 2015;112(2):548–53. doi: 10.1073/pnas.1422456112 25548189

4. Chen H, Yuan H, Gao R, Zhang J, Wang D, Xiong Y, et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet. 2014;383(9918):714–21. doi: 10.1016/S0140-6736(14)60111-2 24507376

5. Hrabal R, Chen Z, James S, Bennett HP, Ni F. The hairpin stack fold, a novel protein architecture for a new family of protein growth factors. Nat Struct Biol. 1996;3(9):747–52. 8784346

6. Chitramuthu BP, Bennett HPJ, Bateman A. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain. 2017;140(12):3081–104. doi: 10.1093/brain/awx198 29053785

7. Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A, et al. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008;118(7):2438–47. doi: 10.1172/JCI34694 18568075

8. Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell. 2002;111(6):867–78. doi: 10.1016/s0092-8674(02)01141-8 12526812

9. He Z, Ong CH, Halper J, Bateman A. Progranulin is a mediator of the wound response. Nat Med. 2003;9(2):225–9. doi: 10.1038/nm816 12524533

10. Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science. 2011;332(6028):478–84. doi: 10.1126/science.1199214 21393509

11. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010;207(1):117–28. doi: 10.1084/jem.20091568 20026663

12. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442(7105):920–4. doi: 10.1038/nature05017 16862115

13. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442(7105):916–9. doi: 10.1038/nature05016 16862116

14. Jian J, Tian QY, Hettinghouse A, Zhao S, Liu H, Wei J, et al. Progranulin Recruits HSP70 to beta-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. EBioMedicine. 2016;13:212–24. doi: 10.1016/j.ebiom.2016.10.010

15. Brandes M, Klauschen F, Kuchen S, Germain RN. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell. 2013;154(1):197–212. doi: 10.1016/j.cell.2013.06.013 23827683

16. Gong Y, Zhan T, Li Q, Zhang G, Tan B, Yang X, et al. Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection, reflecting viral load. Cytokine. 2016;85:26–9. doi: 10.1016/j.cyto.2016.05.026 27281451

17. Suh HS, Lo Y, Choi N, Letendre S, Lee SC. Evidence of the innate antiviral and neuroprotective properties of progranulin. PLoS One. 2014;9(5):e98184. doi: 10.1371/journal.pone.0098184 24878635

18. Gong Z, Lv H, Ding H, Han J, Sun J, Chai C, et al. Epidemiology of the avian influenza A (H7N9) outbreak in Zhejiang Province, China. BMC Infect Dis. 2014;14:244. doi: 10.1186/1471-2334-14-244 24886478

19. Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. 2013;381(9881):1916–25. doi: 10.1016/S0140-6736(13)60903-4 23623390

20. Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol. 2013;14(5):480–8. doi: 10.1038/ni.2563 23525089

21. Song Z, Zhang X, Zhang L, Xu F, Tao X, Zhang H, et al. Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment. Am J Respir Crit Care Med. 2016;194(10):1219–32. doi: 10.1164/rccm.201601-0056OC 27149013

22. Xing J, Weng L, Yuan B, Wang Z, Jia L, Jin R, et al. Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract. Nat Immunol. 2016;17(12):1373–80. doi: 10.1038/ni.3580 27695001

23. Park B, Buti L, Lee S, Matsuwaki T, Spooner E, Brinkmann MM, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity. 2011;34(4):505–13. doi: 10.1016/j.immuni.2011.01.018 21497117

24. Suh HS, Gelman BB, Lee SC. Potential roles of microglial cell progranulin in HIV-associated CNS pathologies and neurocognitive impairment. J Neuroimmune Pharmacol. 2014;9(2):117–32. doi: 10.1007/s11481-013-9495-z 23959579

25. Wei F, Zhang Y, Jian J, Mundra JJ, Tian Q, Lin J, et al. PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci Rep. 2014;4:7023. doi: 10.1038/srep07023 25387791

26. Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol. 2016;18(5):549–60. doi: 10.1038/ncb3340 27088855

27. van Rooijen N, Sanders A, van den Berg TK. Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J Immunol Methods. 1996;193(1):93–9. doi: 10.1016/0022-1759(96)00056-7 8690935

28. Bem RA, Farnand AW, Wong V, Koski A, Rosenfeld ME, van Rooijen N, et al. Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice. Am J Physiol Lung Cell Mol Physiol. 2008;295(2):L314–25. doi: 10.1152/ajplung.00210.2007 18556802

29. Tate MD, Pickett DL, van Rooijen N, Brooks AG, Reading PC. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol. 2010;84(15):7569–80. doi: 10.1128/JVI.00291-10 20504924

30. Luo Q, Yan X, Tu H, Yin Y, Cao J. Progranulin aggravates pulmonary immunopathology during influenza virus infection. Thorax. 2018.

31. Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014;14(5):315–28. doi: 10.1038/nri3665 24762827

32. Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008;29(4):538–50. doi: 10.1016/j.immuni.2008.09.003 18818105

33. Krabbe G, Minami SS, Etchegaray JI, Taneja P, Djukic B, Davalos D, et al. Microglial NFkappaB-TNFalpha hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci U S A. 2017;114(19):5029–34. doi: 10.1073/pnas.1700477114

34. Carrero JA, Calderon B, Unanue ER. Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J Exp Med. 2004;200(4):535–40. doi: 10.1084/jem.20040769 15302900

35. Auerbuch V, Brockstedt DG, Meyer-Morse N, O’Riordan M, Portnoy DA. Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes. J Exp Med. 2004;200(4):527–33. doi: 10.1084/jem.20040976 15302899

36. O’Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, et al. Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med. 2004;200(4):437–45. doi: 10.1084/jem.20040712 15302901

37. Evers BM, Rodriguez-Navas C, Tesla RJ, Prange-Kiel J, Wasser CR, Yoo KS, et al. Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency. Cell Rep. 2017;20(11):2565–74. doi: 10.1016/j.celrep.2017.08.056 28903038

38. Wang X, Li M, Zheng H, Muster T, Palese P, Beg AA, et al. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J Virol. 2000;74(24):11566–73. doi: 10.1128/jvi.74.24.11566-11573.2000 11090154

39. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem. 2009;78:769–96. doi: 10.1146/annurev.biochem.78.070907.102750 19489733

40. Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, et al. NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK. Immunity. 2011;34(6):843–53. doi: 10.1016/j.immuni.2011.02.022

41. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005;6(10):981–8. doi: 10.1038/ni1243 16127453

42. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005;437(7062):1167–72. doi: 10.1038/nature04193 16177806

43. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19(6):727–40. doi: 10.1016/j.molcel.2005.08.014 16153868

44. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4(5):491–6. doi: 10.1038/ni921 12692549.

45. Sankar S, Chan H, Romanow WJ, Li J, Bates RJ. IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. Cell Signal. 2006;18(7):982–93. doi: 10.1016/j.cellsig.2005.08.006 16199137

46. Chen ZJ. Ubiquitination in signaling to and activation of IKK. Immunol Rev. 2012;246(1):95–106. doi: 10.1111/j.1600-065X.2012.01108.x 22435549

47. Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 2009;78:363–97. doi: 10.1146/annurev.biochem.78.082307.091526 19489724

48. Hu H, Sun SC. Ubiquitin signaling in immune responses. Cell Res. 2016;26(4):457–83. doi: 10.1038/cr.2016.40 27012466

49. Sun SC. Deubiquitylation and regulation of the immune response. Nat Rev Immunol. 2008;8(7):501–11. doi: 10.1038/nri2337 18535581

50. Harhaj EW, Dixit VM. Deubiquitinases in the regulation of NF-kappaB signaling. Cell Res. 2011;21(1):22–39. doi: 10.1038/cr.2010.166

51. Maelfait J, Roose K, Bogaert P, Sze M, Saelens X, Pasparakis M, et al. A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection. PLoS Pathog. 2012;8(3):e1002570. doi: 10.1371/journal.ppat.1002570 22396652

52. Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 2008;9(3):263–71. doi: 10.1038/ni1561 18223652

53. Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity. 2010;33(2):181–91. doi: 10.1016/j.immuni.2010.07.017 20705491

54. Chu Y, Vahl JC, Kumar D, Heger K, Bertossi A, Wojtowicz E, et al. B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood. 2011;117(7):2227–36. doi: 10.1182/blood-2010-09-306019 21088135

55. Duwel M, Welteke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, et al. A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. J Immunol. 2009;182(12):7718–28. doi: 10.4049/jimmunol.0803313 19494296

56. Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012;122(11):3955–9. doi: 10.1172/JCI63113 23041626

57. Kawase R, Ohama T, Matsuyama A, Matsuwaki T, Okada T, Yamashita T, et al. Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice. Cardiovasc Res. 2013;100(1):125–33. doi: 10.1093/cvr/cvt178 23847387

58. Tian R, Li Y, Yao X. PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes Through the Wnt/beta-Catenin Signaling Pathway. Inflammation. 2016;39(4):1387–94. doi: 10.1007/s10753-016-0370-y

59. Huang K, Chen A, Zhang X, Song Z, Xu H, Cao J, et al. Progranulin is preferentially expressed in patients with psoriasis vulgaris and protects mice from psoriasis-like skin inflammation. Immunology. 2015;145(2):279–87. doi: 10.1111/imm.12446 25626394

60. Jacques P, Elewaut D. Tumor necrosis factor alpha-induced proteins: natural brakes on inflammation. Arthritis Rheum. 2012;64(12):3831–4. doi: 10.1002/art.34664

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se