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The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response?

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The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response? biomolecules Article The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response? Dominique Leboeuf 1 , Maxim Pyatkov 2 , Timofei S. Zatsepin 1 and Konstantin Piatkov 1,* 1 Skolkovo Institute of Science and Technology, 121205 Moscow, Russia; [email protected] (D.L.); [email protected] (T.S.Z.) 2 Institute of Mathematical Problems of Biology, Keldysh Institute of Applied Mathematics, Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; [email protected] * Correspondence: [email protected] Received: 12 May 2020; Accepted: 12 June 2020; Published: 14 June 2020 Abstract: Recognition of danger signals by a cell initiates a powerful cascade of events generally leading to inflammation. Inflammatory caspases and several other proteases become activated and subsequently cleave their target proinflammatory mediators. The irreversible nature of this process implies that the newly generated proinflammatory fragments need to be sequestered, inhibited, or degraded in order to cancel the proinflammatory program or prevent chronic inflammation. The Arg/N-degron pathway is a ubiquitin-dependent proteolytic pathway that specifically degrades protein fragments bearing N-degrons, or destabilizing residues, which are recognized by the E3 ligases of the pathway. Here, we report that the Arg/N-degron pathway selectively degrades a number of proinflammatory fragments, including some activated inflammatory caspases, contributing in tuning inflammatory processes. Partial ablation of the Arg/N-degron pathway greatly increases IL-1β secretion, indicating the importance of this ubiquitous pathway in the initiation and resolution of inflammation. Thus, we propose a model wherein the Arg/N-degron pathway participates in the control of inflammation in two ways: in the generation of inflammatory signals by the degradation of inhibitory anti-inflammatory domains and as an “off switch” for inflammatory responses through the selective degradation of proinflammatory fragments. Keywords: Arg/N-degron pathway; UBR-ubiquitin ligases; ubiquitin; proteolysis; inflammatory caspases; inflammation 1. Introduction Recognition of a danger signal triggers a coordinated cascade of events, initiating the inflammatory response. In cells of the innate immune system such as neutrophils, granulocytes, or macrophages, danger signals lead to activation of inflammatory caspases (caspases-1, -4, -5, -11, and -12) [1,2] and subsequent proteolysis of a multitude of proinflammatory targets, including IL-1β and various activators of inflammation [3,4]. In the adaptive immune system, cytotoxic T lymphocytes (CTL) and natural killer (NK) cells influence proinflammatory cytokine secretion through the action of granzymes [5,6]. In a more general manner, inflammation can also be initiated through activation of the NF-κB pathway; triggering the transcription of numerous proinflammatory genes; and inducing the production of cytokines, chemokines, and additional proinflammatory mediators [7]. Proinflammatory fragments generated by inflammatory caspases are irreversibly modified, and only sequestration or degradation of the fragments will lead to the resolution of the inflammatory response. Ubiquitylation is known to regulate many inflammatory pathways such as those mediated by Toll-like receptors, NOD-like receptors, and cytokine receptors, all of which can initiate the NF-κB pathway, which is itself being tightly controlled by adding or removing ubiquitin chains [8,9]. Biomolecules 2020, 10, 903; doi:10.3390/biom10060903 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 903 2 of 16 For instance, the processing of NF-κB precursors, activation of the IκB kinase (IKK) complex, andBiomolecules degradation 2020, 10 of, x the NF-κB inhibitor IκB all require ubiquitylation [10,11]. More specifically,2 of 15 when cleaved by calpains during sepsis or other inflammatory settings [12], the NF-κB inhibitor IκBα can bedegradation degraded of by the the NF- Argκ/BN-degron inhibitor I pathway,κB all require due toubiquitylation the presence [10,11]. of the More destabilizing specifically, residue when Glu at the newlycleaved exposed by calpains N-terminus during sepsis [13]. or The other negative inflammatory regulation settings of [12], inflammation the NF-κB inhibitor is generally IκBα provided can by deubiquitinatingbe degraded by the enzymes, Arg/N-degron which pathway, remove due the ubiquitin-activatingto the presence of the destabilizing signal [8,14 ].residue However, Glu at recent the newly exposed N-terminus [13]. The negative regulation of inflammation is generally provided evidence suggests that the resolution of inflammation could also be mediated by E3 ligases and protein by deubiquitinating enzymes, which remove the ubiquitin-activating signal [8,14]. However, recent degradationevidence throughsuggests Lys48-linkedthat the resolution ubiquitin of inflamma chainstion [15 could–17]. also An examplebe mediated is the by controlE3 ligases of and cytokine signalingprotein provided degradation by thethrough E3 ligases Lys48-linked Suppressor ubiquitin of Cytokinechains [15–17]. (SOC) An signaling example is proteins, the control which of are themselvescytokine regulated signaling byprovided ubiquitin-mediated by the E3 ligases degradation Suppressor [18 of]. Cytokine (SOC) signaling proteins, whichThe N-degron are themselves pathway regulated is a proteolyticby ubiquitin-mediated pathway thatdegradation relates the[18].in vivo half-life of a protein to the identityThe of N-degron its N-terminal pathway residue is a proteolytic [19]. N-degrons pathway that comprise relates athe destabilizing in vivo half-life residue, of a protein which to can be recognizedthe identity by an of E3its N-terminal ubiquitin ligase,residue as[19]. well N-degr as anons internal comprise lysine a destabilizing that acts asresidue, the polyubiquitylation which can be site.recognized N-degrons, by generally an E3 ubiquitin formed ligase, after as the well cleavage as an internal of proteins lysine by that exo- acts or as endopeptidases the polyubiquitylation[13,20 –22], site. N-degrons, generally formed after the cleavage of proteins by exo- or endopeptidases [13,20–22], are recognized by specific E3 ubiquitin ligases (N-recognins) that target the proteins for degradation are recognized by specific E3 ubiquitin ligases (N-recognins) that target the proteins for degradation through the proteasome or autophagy [23,24]. In mammals, these E3 ligases are UBR1, UBR2, UBR4, through the proteasome or autophagy [23,24]. In mammals, these E3 ligases are UBR1, UBR2, UBR4, andand UBR5 UBR5 [25 [25].]. The The eukaryote N-degron N-degron pathway pathway consis consiststs of five branches of five branches [19], including [19], the including Arg/N- the Arg/N-degrondegron pathway, pathway, which which targets targets specific specific nonacetyla nonacetylatedted N-terminal N-terminal residues residues(Figure 1) (Figure [26]. The1)[ 26]. Theprimary destabilizing destabilizing N-terminal N-terminal residues residues are direct arely recognized directly recognized by E3 ligases, by whereas E3 ligases, N-terminal whereas N-terminalAsp, Glu, Asp, Asn, Glu,Gln, and Asn, Cys Gln, amino and acids Cys function amino as acids destabilizing function residues as destabilizing through their residues preliminary through theirmodifications, preliminary modifications,such as N-terminal such arginylation as N-terminal by the arginylation ATE1 arginyl-transferase by the ATE1 arginyl-transferase(R-transferase) (R-transferase)(Figure 1) [26,27]. (Figure 1)[26,27]. Figure 1. The mammalian Arg/N-degron pathway. N-terminal residues are indicated by single-letter abbreviationsFigure 1. The for mammalian amino acids, Arg/N-degron and the rest pathway. of a protein N-termin substrateal residues is representedare indicated by single-letter orange spheres. “Primary”,abbreviations “secondary”, for amino andacids, “tertiary” and the rest denote of a pr mechanisticallyotein substrate is represented distinct subsets by orange of destabilizingspheres. N-terminal“Primary”, residues. “secondary”, C* denotesand “tertiary” oxidized denote N-terminal mechanistically Cys, distinct either su Cys-sulfinatebsets of destabilizing or -sulfonate. N- The mammalianterminal residues. N-recognins C* denotes UBR1, oxidized UBR2, N-terminal UBR4, and Cys, UBR5 either (EDD) Cys-sulfin have multipleate or -sulfonate. substrate-binding The sitesmammalian that recognize N-recognins internal UBR1, and terminalUBR2, UBR4, N-degrons and UBR5 and (EDD) target have them multiple to thesubstrate-binding proteasome. sites MetAPs: methioninethat recognize aminopeptidase, internal and NTAN1: terminal N-terminal N-degron asparagines and target amidohydrolase, them to the proteasome. and NTAQ1: MetAPs: N-terminal glutaminemethionine amidohydrolase aminopeptidase, (adapted NTAN1: from N-terminal [21]). asparagine amidohydrolase, and NTAQ1: N- terminal glutamine amidohydrolase (adapted from [21]). Through the selective degradation of proteins, the mammalian Arg/N-degron pathway mediates multipleThrough biological the functions, selective degradation including theof proteins regulation, the mammalian of apoptosis, Arg/N-degron repression pathway of neurodegeneration, mediates multiple biological functions, including the regulation of apoptosis, repression of neurodegeneration, the elimination of aberrant proteins during stress, as well as the regulation of vascular development Biomolecules 2020, 10, 903 3 of 16 and cell motility ([19] and references therein). The regulation
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