Dysregulation of protein modification by ISG15 results in brain cell injury

Ritchie, Kenneth J.; Malakhov, Michael P.; Hetherington, Christopher J.; Zhou, Liming; Little, Michelle; Malakhova, Oxana A.; Sipe, Jack C.; Orkin, Stuart H.; Zhang, Dong‐Er

doi:10.1101/gad.1010202

Cited by 148 publications

(127 citation statements)

References 40 publications

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“…It seems that tight regulation of both the ISG15 conjugation and deconjugation pathways is required to ensure proper response to cellular stress. In UBP43 knockout mouse embryonic fibroblasts (MEFs), ISG15 cleavage from cellular substrates is strongly reduced, suggesting that UBP43 is the major ISG15 isopeptidase (17). UBP43Ϫ/Ϫ MEFs demonstrate prolonged STAT1 signaling and IFN hypersensitivity, which is in accordance with data showing that signal transducer and activator of transcription 1 is an ISG15-modified protein (18).…”

supporting

confidence: 75%

The ISG15 Isopeptidase UBP43 Is Regulated by Proteolysis via the SCFSkp2 Ubiquitin Ligase

Tokarz

Berset²,

Rue

et al. 2004

Journal of Biological Chemistry

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The Skp2 oncoprotein belongs to the family of F-box proteins that function as substrate recognition factors for SCF (Skp1, cullin, F-box protein) E3 ubiquitin-ligase complexes. Binding of the substrate to the SCF Skp2 complex catalyzes the conjugation of ubiquitin molecules to the bound substrate, resulting in multi-ubiquitination and rapid degradation by the 26 S proteasome. Using Skp2 as bait in a yeast two-hybrid screen, we have identified UBP43 as a novel substrate for Skp2. UBP43 belongs to the family of ubiquitin isopeptidases and specifically cleaves ISG15, a ubiquitin-like molecule that is induced by cellular stresses, such as type 1 interferons (IFN), nephrotoxic damage, and bacterial infection. UBP43 was originally identified as an up-regulated gene in knock-in mice expressing an acute myelogenous leukemia fusion protein, AML1-ETO, as well as in melanoma cell lines treated with IFN-␤. The phenotype of UBP43 knockout mice includes shortened life span, hypersensitivity to IFN, and neuronal damage, suggesting that tight regulation of ISG15 conjugation is critical for normal cellular function. In this study, we demonstrate that UBP43 is ubiquitinated in vivo and accumulates in cells treated with proteasome inhibitors. We also show that Skp2 promotes UBP43 ubiquitination and degradation, resulting in higher levels of ISG15 conjugates. In Skp2؊/؊ mouse cells, levels of UBP43 are consistently up-regulated, whereas levels of ISG15 conjugates are reduced. Our results demonstrate that the SCF Skp2 is involved in controlling UBP43 protein levels and may therefore play an important role in modulating type 1 IFN signaling.Modification of proteins by ubiquitin and ubiquitin-like (Ubl) 1 molecules, including SUMO, Nedd8, and ISG15, has emerged as a critical regulatory process in eukaryotes, controlling pathways such as the cell cycle, cellular stress response, intracellular signaling, development, and the immune response (1-5). Deregulation of ubiquitin or Ubl modification can cause autoimmune and neurodegenerative diseases, developmental abnormalities, and cancer.Conjugation of ubiquitin and Ubls involves a three-step mechanism initially demonstrated for ubiquitin as follows. A single E1 ubiquitin-activating enzyme activates the Ubl molecule via formation of a thioester bond. Activated Ubl is then transferred to one of a large family of E2 ubiquitin-conjugating enzymes. In most cases, E2 enzymes are targeted to appropriate substrates by a class of substrate receptor complexes termed E3 ubiquitin ligases. Together, the E2 and E3 enzymes catalyze the formation of isopeptide bonds between ubiquitin and lysine residues on the target proteins. In the case of multiubiquitination, additional ubiquitin molecules are added to form ubiquitin chains. The multiubiquitinated proteins are then recognized and rapidly degraded into short peptides by the 26 S proteasome (3, 6). Modification by ubiquitin and Ubl molecules is a reversible process mediated by a large family of isopeptidases that exist to remove these molecules from the...

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supporting

confidence: 75%

The ISG15 Isopeptidase UBP43 Is Regulated by Proteolysis via the SCFSkp2 Ubiquitin Ligase

Tokarz

Berset²,

Rue

et al. 2004

Journal of Biological Chemistry

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“…The roles of different IFN-regulated genes in CNS physiology and pathophysiology such as neurodevelopment, regulation of temperature, sleep, food intake and emotion remain to be explored. In this regard, a recent study found that depletion of a newly identified IFN-stimulated gene USP18 (also named ubiquitin-specific protease 43), in which expression in brain was highly activated by peripheral IFN-a injection in our study ( Figures 1 and 4), results in the development of a severe neurological disorder. 43 Despite intense studies and the development of various drug therapies, the etiopathogenesis for common human mental disorders such as affective disorders, anxiety and schizophrenia remains poorly understood.…”

Section: Discussionsupporting

confidence: 54%

“…In this regard, a recent study found that depletion of a newly identified IFN-stimulated gene USP18 (also named ubiquitin-specific protease 43), in which expression in brain was highly activated by peripheral IFN-a injection in our study ( Figures 1 and 4), results in the development of a severe neurological disorder. 43 Despite intense studies and the development of various drug therapies, the etiopathogenesis for common human mental disorders such as affective disorders, anxiety and schizophrenia remains poorly understood. 44,45 However, recent clinical observations from patients on IFN-a therapy 10,11 and genetic studies on autoimmune mice 46 suggest a direct link between IFN-a and neuropsychiatric disorders.…”

Section: Discussionsupporting

confidence: 54%

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

2007

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The prime anti-viral cytokine interferon-a (IFN-a) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-a treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-a have been described, it remains unresolved whether or not systemic IFN-a acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-a receptor signaling and found that intraperitoneal administration of mouse IFN-a, but not human IFN-a, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-aactivated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-a challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-a in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-a therapy.

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“…As reported previously, IFN production upon LPS treatment is due to the phosphorylation of IRF3 via a Trif pathway and the induction of NF-B via a MyD88 pathway (15). We previously generated UBP43 knockout mice to study the biological function of the protein ISGylation system (6,26). We used this mouse model to investigate the possible involvement of ISGylation or UBP43 in response to LPS-mediated TLR4 signaling.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

Kim¹,

Malakhova²,

Hoebe

et al. 2005

The Journal of Immunology

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ISG15 is an IFN-inducible ubiquitin-like protein and its expression and conjugation to target proteins are dramatically induced upon viral or bacterial infection. We have generated a UBP43 knockout mouse model that is lacking an ISG15-specific isopeptidase to study the biological role of the protein ISGylation system. We report that UBP43-deficient mice are hypersensitive to LPS-induced lethality and that TIR domain-containing adapter inducing IFN-β → IFN regulatory factor 3 → type I IFN is the major axis to induce protein ISGylation and UBP43 expression in macrophages upon LPS treatment. In ubp43−/− macrophages, upon LPS treatment we detected increased expression of IFN-stimulated genes, including genes for several cytokines and chemokines involved in the innate immune response. The ubp43−/− mice were able to restrict the growth of Salmonella typhimurium more efficiently than wild-type mice. These results clearly demonstrate two aspects of IFN-signaling, a beneficial effect against pathogens but a detriment to the body without strict control.

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Dysregulation of protein modification by ISG15 results in brain cell injury

Cited by 148 publications

References 40 publications

The ISG15 Isopeptidase UBP43 Is Regulated by Proteolysis via the SCFSkp2 Ubiquitin Ligase

The ISG15 Isopeptidase UBP43 Is Regulated by Proteolysis via the SCFSkp2 Ubiquitin Ligase

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

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