ISG15 and ISGylation Regulate the Host Response to Viral Infections
Received Date: Jun 28, 2018 / Accepted Date: Jun 29, 2018 / Published Date: Jun 30, 2018
During viral infection, the host innate immune response provides early protection. To control virus spread, the host cells produce type I interferons (IFNs) as first line of defense, acting as antiviral and inflammatory cytokines. Type I IFNs binding with interferon α/β receptor (IFNAR) triggers the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway to induce the synthesis of a few hundred IFN-stimulated genes (ISGs) which inhibit virus replication at different steps of the virus replication cycle . Ubiquitin-like protein ISG15 is one of the most strongly and promptly induced ISG following virus infection, and many studies have demonstrated that ISG15 can directly inhibit viral replication and modulate host immune response. ISG15 is one of the members of ubiquitin families, which include ubiquitin and ubiquitin-like modifiers (Ubls). ISG15 can covalently conjugate to target proteins via isopeptide bonds and this conjugation process of protein modification is known as ISGylation which is involved in the regulation of many cellular processes. To date, proteomic studies have identified a few hundred ISG15 target proteins [2,3]. Research of specific ISG15 targeted proteins have found that through competing with ubiquitin binding sites, ISG15 can inhibit protein ubiquitination, indirectly regulating protein degradation .
ISGylation can be reversed by the deconjugating enzyme Ubl carboxy-terminal hydrolase 18 (USP18), also known as UBP43 . USP18 is a protease that can efficiently cleave ISG15 from its conjugated target ptoteins. In addition, independent of its deconjugating activity, USP18 also functions as a negative regulator of interferon signalling via competing with Janus kinase 1 (JAK1) to bind to the second chain of IFNAR2 complex . Many studies have broadened our understanding on how ISG15 and ISGylation regulate viral replication and modulate host immune response.
Effects of ISG15 on viral replication and egress
Previous studies have shown that ISGylation of viral proteins could disrupt viral replication. Zhao et al. found that ISG15 inhibits influenza A virus (IAV) replication by conjugating to a specific viral protein NS1, the critical virulence factor of IAV, in virus-infected cells . Later, Tang et al. reported that ISG15 conjugation onto IAV-NS1 protein prevents the formation of NS1 homodimers, and limits its ability to disrupt the antiviral response . Another study found that ISGylation of avian infectious bronchitis virus (IBV) NP blocks oligomerization which reduces IBV replication. Similarly, human papillomavirus (HPV) capsid protein 1 can be ISGylated and the number and infectivity of viral particles were decreased . In addition, the ISGylation of coxsackievirus B3 (CVB3) protease 2A (2APro) inhibits the cleavage of eIF4G during CVB3 infection which in turn reduce viral replication . These data collectively demonstrated that ISGylation of viral proteins could disrupt viral protein function or inhibit the oligomerization of viral proteins to inhibit viral replication. Furthermore, ISGylated viral proteins fail to interact with host signaling pathways to alter the host antiviral response. Study from Kim et al. has shown that ISGylation inhibits human cytomegalovirus (HCMV) replication in multiply stages . These data illustrate ISG15 binding with viral proteins could inhibit viral replication.
Several studies have found that ISG15 affects virus egress through modulating specific host proteins. Okumura et al. first reported that ISG15 inhibits ubiquitination of HIV Gag and Tsg101 and disrupts their interaction to inhibit HIV-1 release . Later another group also found that ISGylation of Tsg101 inhibits the transportation of IAV hemagglutinin (HA) . Moreover, ISG15 conjugation triggers multivesicular bodies (MVB) to co-localize with lysosomes which decreases MVB numbers and impairs exosome secretion . A recent study found that the E3 ubiquitin ligase, ITCH, interacts with Ebola VP40 to regulate viral budding via an identical budding domain that is used by another E3 ubiquitin ligase NEDD4 . These studies demonstrated that ISGylation of viral and host proteins that are involved in protein sorting and transport pathways is required for viral egress.
The role of ISG15 in immune modulation during viral infection
Previous studies have shown that recombinant ISG15 could stimulate IFNγ production, stimulate NK cell proliferation, dentritic cell maturation and recruit neutrophil . Recently, LFA1 was identified as a cell surface receptor for ISG15, and in IL-12 treated cells the binding of LAF1 with ISG15 mediated the release of IFNγ and IL-10 . Whether these immune modulation effects are mediated by intracellular or extracellular ISG15 remain to be determined. Nevertheless, these findings demonstrated that unconjugated ISG15 negatively regulates cytokine and chemokine production during certain viral infections.
Recent findings support ISG15 in the regulation of disease tolerance during IAV and Sendai virus infection (SeV) in a mouse model, and identified ISG15 targets pathways involved in apoptosis and autophagy [18,19]. Besides, proteomic studies have identified ISG15 targets hundreds of host proteins upon interferon stimulation [2,3]. Many of these are ISGs that are involved in the regulation of the innate immune response and host antiviral response, such as RIG-I, MxA, PKR, STAT1 and JAK1 .
Most recently, ISG15 has been widely known as an anti-viral protein against viral infections. ISG15 inhibits viral replication and increases the number of viral immune-evasion proteins through modulating viral and host proteins. In addition, ISG15 can also regulate cytokine responses, host damage and repair response and autophagy and metabolism. Still there are many important questions need to be answered, like what is the function of extracellular ISG15 during viral infection? How the ISGylated proteins affect the overall function in cells? Further studies on ISGylation pathway may identify new targets to control diseases progression, and to provide promising targets for antivirus treatment.
- Wong MT, Chen SS (2016) Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection. Cell Mol Immunol 13: 11-35.
- Giannakopoulos NV, Luo JK, Papov V, Zou W, Lenschow DJ, et al. (2005) Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. Biochem Biophys Res Commun 336: 496-506.
- Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM (2005) Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci USA 102: 10200-10205.
- Desai SD, Haas AL, Wood LM, Tsai YC, Pestka S, et al. (2006) Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Cancer Res 66: 921-928.
- Basters A, Geurink PP, Rocker A, Witting KF, Tadayon R, et al. (2017) Structural basis of the specificity of USP18 toward ISG15. Nat Struct Mol Biol 24: 270-278.
- Malakhova OA, Kim KI, Luo JK, Zou W, Kumar SKG, et al. (2006) UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J 25: 2358-2367.
- Zhao C, Hsiang TY, Kuo RL, Krug RM (2010) ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci USA 107: 2253-2258.
- Tang Y, Zhong G, Zhu L, Liu X, Shan Y, et al. (2010) Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein. J Immunol 184: 5777-5790.
- Durfee LA, Lyon N, Seo K, Huibregtse JM (2010) The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol Cell 38: 722-732.
- Rahnefeld A, Klingel K, Schuermann A, Diny NL, Althof N, et al. (2014) Ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) in host defense against heart failure in a mouse model of virus-induced cardiomyopathy. Circulation 130: 1589-1600.
- Kim YJ, Kim ET, Kim YE, Lee MK, Kwon KM, et al. (2016) Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators. PLoS Pathog 12: e1005850.
- Okumura A, Lu G, Pitha-Rowe I, Pitha PM (2006) Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15. Proc Natl Acad Sci U S A 103: 1440-1445.
- Sanyal S, Ashour J, Maruyama T, Altenburg AF, Cragnolini JJ, et al. (2013) Type I interferon imposes a TSG101/ISG15 checkpoint at the Golgi for glycoprotein trafficking during influenza virus infection. Cell Host & Microbe 14: 510-521.
- Villarroya-Beltri C, Baixauli F, Mittelbrunn M, Fernández-Delgado I1, Torralba D, et al. (2016) ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat Commun 7: 13588.
- Han Z, Sagum CA, Bedford MT, Sidhu SS, Sudol M, et al. (2016). ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding. J Virol 90: 9163-9171.
- Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, et al. (2012) Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science 337: 1684-1688.
- Swaim CD, Scott AF, Canadeo LA, Huibregtse JM (2017) Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Mol Cell 68: 581-590.e5.
- Xu D, Zhang T, Xiao J, Zhu K, Wei R, et al. (2015) Modification of BECN1 by ISG15 plays a crucial role in autophagy regulation by type I IFN/interferon. Autophagy 11: 617-628.
- Falvey CM, O'Donovan TR, El-Mashed S, Nyhan MJ, O'Reilly S (2017) UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells. Oncotarget 8: 23479-23491.
Citation: Li S, Li S, Chen L (2018) ISG15 and ISGylation Regulate the Host Response to Viral Infections. J Antivir Antiretrovir 10:LXXXiv-LXXXv. DOI: 10.4172/1948-5964.1000e141
Copyright: © 2018 Li S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
October 29-30, 2018 San Francisco, USA
December 3-4, 2018 Chicago, USA
- Total views: 1772
- [From(publication date): 0-2018 - Sep 23, 2018]
- Breakdown by view type
- HTML page views: 1735
- PDF downloads: 37