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Ubiquitin-like protein ISG15

Definition:

Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL.

References:

[1]. E Knight Jr, et al. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. [Content Brief]

[2]. Tomoharu Takeuchi, et al. Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation. FEBS Lett. 2006 Aug 7;580(18):4521-6. [Content Brief]

[3]. Veronika N Bade, et al. Covalent protein modification with ISG15 via a conserved cysteine in the hinge region. PLoS One. 2012;7(6):e38294. [Content Brief]

[4]. K R Loeb, et al. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. [Content Brief]

[5]. Caleb D Swaim, et al. Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Mol Cell. 2017 Nov 2;68(3):581-590.e5. [Content Brief]

[6]. K R Loeb, et al. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. [Content Brief]

[7]. Zhizhou Kuang, et al. Mechanism of inhibition of retrovirus release from cells by interferon-induced gene ISG15. J Virol. 2011 Jul;85(14):7153-61. [Content Brief]

[8]. Tomoharu Takeuchi, et al. ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity. Biochem Biophys Res Commun. 2005 Oct 14;336(1):9-13. [Content Brief]

[9]. Dusan Bogunovic, et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science. 2012 Sep 28;337(6102):1684-8. [Content Brief]

[10]. He-Xin Shi, et al. Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification. Mol Cell Biol. 2010 May;30(10):2424-36. [Content Brief]

[11]. J Narasimhan, et al. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. [Content Brief]

[12]. Chen Zhao, et al. ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2253-8. [Content Brief]

[13]. Young Joo Jeon, et al. ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway. EMBO Rep. 2009 Apr;10(4):374-80. [Content Brief]

[14]. Tien-Ying Hsiang, et al. Interferon-induced ISG15 conjugation inhibits influenza A virus gene expression and replication in human cells. J Virol. 2009 Jun;83(12):5971-7. [Content Brief]

[15]. Atsushi Okumura, et al. Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1440-5. [Content Brief]

[16]. Ruth Broering, et al. The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response. Gut. 2010 Aug;59(8):1111-9. [Content Brief]

[17]. Atsushi Okumura, et al. ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3974-9. [Content Brief]

[18]. GuanQun Liu, et al. ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat Microbiol. 2021 Apr;6(4):467-478. [Content Brief]

[19]. Tomoharu Takeuchi, et al. Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme. J Biochem. 2005 Dec;138(6):711-9. [Content Brief]

[20]. Chen Zhao, et al. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. [Content Brief]

[21]. Fumihiko Okumura, et al. Activation of double-stranded RNA-activated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation. J Biol Chem. 2013 Jan 25;288(4):2839-47. [Content Brief]

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