ISG15 in antiviral immunity and beyond

Perng, Yi-Chieh; Lenschow, Deborah J.

doi:10.1038/s41579-018-0020-5

Cited by 615 publications

(586 citation statements)

References 170 publications

(153 reference statements)

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“…Speer et al suggest that ISGylation may sequester free ISG15 early in infection to activate IFN, and only late in infection does USP18 become stabilized by free ISG15 to dampen IFN response. The role of free ISG15 and ISGylation in viral pathogenesis remains complex especially since free ISG15 is a negative regulator of IFN-signaling in humans (Perng and Lenschow, 2018). Interestingly, viruses have been shown to modulate the system by upregulating the process of deISGylation and increasing pools of ISG15, which could impact IFN activation.…”

Section: Introductionmentioning

confidence: 99%

Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease

et al. 2020

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A B S T R A C TCoronavirus papain-like proteases (PLPs or PLpro), such as the one encoded in the genome of the infectious Middle East Respiratory Syndrome (MERS) virus, have multiple enzymatic activities that promote viral infection. PLpro acts as a protease and processes the large coronavirus polyprotein for virus replication. PLpro also functions as both a deubiquitinating (DUB) and deISGylating (deISG) enzyme and removes ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) from cellular proteins. Both DUB and deISG activities are implicated in suppressing innate immune responses; however, the precise role of each activity in this process is still unclear due in part to the difficulties in separating each activity. In this study, we determine the first structure of MERS PLpro in complex with the full-length human ISG15 to a resolution of 2.3 Å. This structure and available structures of MERS PLpro-Ub complexes were used as molecular guides to design PLpro mutants that lack either or both DUB/deISG activities. We tested 13 different PLpro mutants for protease, DUB, and deISG activitites using fluorescence-based assays. Results show that we can selectively modulate DUB activity at amino acid positions 1649 and 1653 while mutation of Val1691 or His1652 of PLpro to a positive charged residue completely impairs both DUB/deISG activities. These mutant enzymes will provide new functional tools for delineating the importance of DUB versus deISG activity in virus-infected cells and may serve as potential candidates for attenuating the MERS virus in vivo for modified vaccine design efforts.

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Section: Introductionmentioning

confidence: 99%

Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease

et al. 2020

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“…This group of proteins includes ISG15 that has a diubiquitin-like structure (2). Isg15 is one of the genes most strongly upregulated in response to viral infection in a diversity of species, including humans (3,4). ISG15 is also induced by bacterial infections (5,6).…”

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confidence: 99%

“…ISG15 is also induced by bacterial infections (5,6). Isg15-deficient mice and humans display phenotypes that indicate a role for ISG15 in the protection against infection, but the underlying mechanisms have not been fully elucidated (3,7,8). ISG15 can be conjugated to proteins but also exists in a free form and thus may act by different mechanisms either within or outside the cell.…”

mentioning

confidence: 99%

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

Iglesias-Guimarais

Ahrends

Vries

et al. 2020

The Journal of Immunology

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Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a “cytokine” are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8+ T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4+ T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response.

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“…In mice, ISG15 plays an important role in host response to viral infection. It has been shown to protect from viral-induced lethality using different pathogens (Perng and Lenschow, 2018). However, ISG15-null patients appear not to be more susceptible to viral infections (Bogunovic et al, 2012).…”

Section: Isg15-and Usp18-related Diseasesmentioning

confidence: 99%

“…As in infected cells mainly viral proteins are translated, ISGylation can interfere with pathogen protein function as shown for capsid assembly of the papilloma virus (Durfee et al, 2010). Furthermore, cellular proteins involved in antiviral defense or export of viral particles were shown to be ISGylated (Perng and Lenschow, 2018).…”

Section: Introductionmentioning

confidence: 99%

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

2020

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The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

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ISG15 in antiviral immunity and beyond

Cited by 615 publications

References 170 publications

Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease

Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

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