ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis

viruses Review ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis Manuel Albert † , Martina Bécares †, Michela Falqui, Carlos Fernández-Lozano and Susana Guerra * Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma, E-28029 Madrid, Spain; [email protected] (M.A.); [email protected] (M.B.); [email protected] (M.F.); [email protected] (C.F.-L.) * Correspondence: [email protected]; Tel.: +34-91/497-5440; Fax: +34-91/497-5353 † These authors contributed equally. Received: 26 October 2018; Accepted: 9 November 2018; Published: 13 November 2018 Abstract: Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the scientific community, as we are still far from understanding the molecular mechanisms that operate after virus infection. Interferon-stimulated gene 15 (ISG15) plays an important antiviral role during viral infection. ISG15 catalyzes a ubiquitin-like post-translational modification termed ISGylation, involving the conjugation of ISG15 molecules to de novo synthesized viral or cellular proteins, which regulates their stability and function. Numerous biomedically relevant viruses are targets of ISG15, as well as proteins involved in antiviral immunity. Beyond their role as cellular powerhouses, mitochondria are multifunctional organelles that act as signaling hubs in antiviral responses. In this review, we give an overview of the biological consequences of ISGylation for virus infection and host defense. We also compare several published proteomic studies to identify and classify potential mitochondrial ISGylation targets. Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy. Keywords: interferon; ubiquitin-like modification; mitochondria; mitophagy; OXPHOS 1. Introduction 1.1. ISG15 Definition The innate immune response is the first line of defense against microbial and viral infections. Invading microorganisms produce danger- and pathogen-associated molecular patterns that interact with host pattern-recognition receptors, triggering several intracellular signaling cascades that activate nuclear factor kappa-B (NF-κB), mitogen-activated protein kinases (MAPKs) and interferon (IFN) regulatory factors (IRFs), resulting in the expression of a broad array of proteins involved in host defense such as type-I IFNs and proinflammatory cytokines [1,2]. The release of type-I IFNs has both autocrine and paracrine effects via IFNα/β receptors (IFNARs) on the cell surface. Binding to IFNARs leads to the activation of the Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT) signaling pathway and the formation of the interferon-stimulated gene factor 3 (ISGF3) complex, with the subsequent expression of IFN-stimulated genes [3] that establish an antiviral state and play important roles in determining the host innate and adaptive immune responses [4]. One of the most highly induced genes in the type-I IFN signaling cascade is ISG15 (interferon-stimulated gene 15), which encodes a small ubiquitin-like protein involved in a post-translational modification Viruses 2018, 10, 629; doi:10.3390/v10110629 www.mdpi.com/journal/viruses Viruses 2018, 10, x FOR PEER REVIEW 2 of 17 Viruses 2018, 10, 629 2 of 18 One of the most highly induced genes in the type‐I IFN signaling cascade is ISG15 (interferon‐ stimulated gene 15), which encodes a small ubiquitin‐like protein involved in a post‐translational (PTM)modification process (PTM) termed process ISGylation. termed Through ISGylation. this process, Through ISG15 this covalently process, binds ISG15 to covalently a wide range binds of target to a proteinswide range [5]. of ISG15 target exists proteins in three [5]. ISG15 different exists forms: in three unconjugated different forms: within unconjugated the cell, conjugated within to the target cell, proteins,conjugated and to released target proteins, into the serumand released (Figure into1). ISG15the serum is synthesized (Figure 1). asISG15 a 17-kDa is synthesized precursor as that a 17 is‐ proteolyticallykDa precursor that processed is proteolytically into a mature processed form of into 15 kDa.a mature This form processing of 15 kDa. exposes This aprocessing carboxy-terminal exposes LRLRGGa carboxy‐ motif,terminal required LRLRGG for motif, ISGylation required [6] (Figurefor ISGylation1). ISGylation [6] (Figure is the 1). result ISGylation of the is coordination the result of ofthe three coordination enzymatic of activities-activation,three enzymatic activities conjugation‐activation, and ligation—performedconjugation and ligation—performed by ISG15-activating by enzymesISG15‐activating (E1), ISG15-conjugating enzymes (E1), ISG15 enzymes‐conjugating (E2) and enzymes ISG15-ligating (E2) and enzymes ISG15‐ligating (E3), respectively enzymes (E3), [7] (Figurerespectively1). Considering [7] (Figure 1). the Considering broad substrate the broad selectivity substrate described selectivity for ISGylation,described for and ISGylation, the fact that and Herc5the fact (the that major Herc5 ISG15-ligating (the major ISG15 enzyme)‐ligating associates enzyme) with associates polyribosomes, with polyribosomes, it has been established it has been that ISGylationestablished targetsthat ISGylation proteins undergoingtargets proteins active undergoing translation active [8]. In translation the context [8]. of In viral the infection,context of those viral newlyinfection, synthesized those newly proteins synthesized are largely proteins viral are proteins largely andviral cellular proteins proteins and cellular involved proteins in the involved innate immunein the innate response. immune response. Figure 1. Intracellular and extracellular activities of ISG15. Different stimuli trigger the expression of ISG15, which which is is produced produced as as a precursor a precursor of 17 of kDa 17 kDa with with two twoubiquitin ubiquitin-like‐like domains domains linked linked by a hinge by a hingeregion region (1). Intracellular (1). Intracellular ISG15 ISG15 can be can processed be processed into into its itsmature mature form form and and conjugated conjugated to to dede novo synthesized proteins in a process termedtermed ISGylation.ISGylation. ISG15 processing exposes its carboxy-terminalcarboxy‐terminal LRLRGG motif,motif, allowing allowing its its conjugation conjugation to lysineto lysine residues residues in target in target proteins proteins to modulate to modulate their function. their Infunction. addition, In addition, ISGylation ISGylation is reversible is reversible due to the due action to the of theaction protease of the USP18,protease which USP18, also which regulates also IFNAR-mediatedregulates IFNAR‐mediated signaling signaling (2). ISG15 (2). can ISG15 remain can unconjugated remain unconjugated within the within cell, the regulating cell, regulating protein activityprotein activity (3), or be (3), secreted or be secreted as a cytokine, as a cytokine, acting as acting a chemotactic as a chemotactic and stimulating and stimulating factor for factor immune for cellsimmune (4). Bindingcells (4). of Binding ISG15 toof LFA-1ISG15 integrinto LFA‐1 receptor integrin on receptor the surface on the of surface NK cells of promotes NK cells thepromotes activation, the productionactivation, production and release and of IFN- releaseγ IL-10 of IFN after‐γ IL IL-12‐10 after priming. IL‐12 Moreover, priming. Moreover, extracellular extracellular ISG15 is able ISG15 to formis able dimers/multimers to form dimers/multimers through cysteinethrough residues,cysteine residues, to modulate to modulate cytokine levels.cytokine levels. ISG15 conjugation to target proteins is a covalent and reversible process through the action of a 43-kDa43‐kDa deISGylasedeISGylase enzyme, enzyme, ubiquitin-specific ubiquitin‐specific protease protease 18 18 (USP18) (USP18) [9, 10[9,10].]. Interestingly, Interestingly, both both ISG15 ISG15 and itsand conjugating its conjugating and deconjugating and deconjugating enzymes enzymes are upregulated are upregulated by type-I by IFNtype [‐9I ],IFN as well [9], as as well by other as by stimuli other suchstimuli as type-IIsuch as and type type-III‐II and IFNs type‐ [III11 –IFNs13], lipopolysaccharide [11–13], lipopolysaccharide [14], retinoic [14], acid retinoic [15], DNA acid damage[15], DNA or genotoxicdamage or reagents genotoxic [16 ].reagents USP18 not [16]. only USP18 acts as not a deconjugating only acts as a enzyme, deconjugating but also enzyme, as a negative but regulatoralso as a ofnegative the type-I regulator IFN pathwayof the type (Figure‐I IFN 1pathway), with important(Figure 1), implicationswith important in implications antiviral and in antibacterial antiviral and responses,antibacterial immune responses, cell development,immune cell development, autoimmune autoimmune diseases and diseases cancer [17 and]. In cancer humans, [17]. ISG15 In humans, binds toISG15 USP18, binds increasing to USP18, its stability increasing and leadingits stability to a decreaseand leading in IFN- toα a/ βdecreasesignaling. in Consequently, IFN‐α/β signaling. ISG15 deficiencyConsequently, results ISG15 in low deficiency USP18 levels, results

Load more