Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Hamerman, Jessica A.; Hayashi, Fumitaka; Schroeder, Lea; Gygi, Steven P.; Haas, Arthur; Hampson, Lynne; Coughlin, Paul; Aebersold, Ruedi; Aderem, Alan

doi:10.4049/jimmunol.168.5.2415

Cited by 86 publications

(61 citation statements)

References 53 publications

(48 reference statements)

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“…Their target enzymes regulate very diverse processes, including apoptosis, inflammation and neoplasia (Gettins, 2000). Its expression has been shown to be strongly induced by IFN-c and in vivo by intracellular bacteria such as Mycobacterium bovis bacille Calmette-Guérin (BCG), L. monocytogenes and Salmonella typhimurium, and by bacterial products like LPS or peptidoglycan (Hamerman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Andersson

Hartmanová

KuoLee

et al. 2006

Journal of Medical Microbiology

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Tularaemia caused by inhalation of type A Francisella tularensis bacteria is one of the most aggressive infectious diseases known, but the reasons for the very rapid spread of the organism from the lungs to internal organs and the ensuing mortality are unknown. The present study used the mouse model to examine in detail the host immune response in the lung. After an aerosol challenge with 20 c.f.u. of the type A strain FSC033, all mice developed clinical signs of severe disease, showed weight loss by day 4 of infection and died the next day. Histopathological findings in the lung revealed acute inflammation and intense vasculitis and perivasculitis on day 4. Gene transcriptional changes in the mouse lung samples were examined on days 1, 2 and 4 of infection using a cDNA microarray with 20 600 mouse clones representing 18 500 genes. In total, 424 genes were found to be differentially expressed, some of which were both up-and downregulated at different time points, 192 of which were upregulated and 234 of which were downregulated for at least one time point. A high percentage of selected genes identified by the microarray analysis were confirmed to be differentially regulated by quantitative real-time PCR. Categorization of the differentially expressed genes showed that those preferentially involved in host immune responses were activated extensively on day 4 but hardly or not at all on days 1 and 2. Further analysis revealed that several of the genes upregulated on day 4 are known to depend on gamma interferon or tumour necrosis factor alpha for their regulation. In keeping with this finding, tumour necrosis factor alpha and gamma interferon levels were found to be increased significantly in bronchoalveolar lavage on day 4.

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Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Andersson

Hartmanová

KuoLee

et al. 2006

Journal of Medical Microbiology

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“…In the absence of UBP43, cells accumulate much higher levels of ISGylated proteins. To date, only five cellular targets for protein ISGylation have been reported, including Serpin 2a, Jak1, Stat1, phospholipase C␥1, and Erk1/2 (28,44), among possibly hundreds of ISGylated proteins. We recently report that UBP43-deficient mice are resistant to certain virus infections (45).…”

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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“…Expression of ISG15 is inducible by alpha/beta interferons. ISG15 has multiple targets, of which a limited number, i.e., serpin 2A, phospholipase C␥1, Jak1, ERK1, and STAT1, have been identified to date (21,40,42). In the cell, ISG15 colocalizes with intermediate filaments and ISGylation may be involved in certain aspects of neurological disease or function and may modulate signaling through the JAK-STAT pathway (39,42,55).…”

mentioning

confidence: 99%

Specific and Covalent Targeting of Conjugating and Deconjugating Enzymes of Ubiquitin-Like Proteins

Hemelaar

Borodovsky

Kessler

et al. 2004

Molecular and Cellular Biology

188

180

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Modification of proteins by ubiquitin (Ub)-like proteins (UBLs) plays an important role in many cellular processes, including cell cycle progression, nuclear transport, and autophagy. Protein modification occurs via UBL-conjugating and -deconjugating enzymes, which presumably exert a regulatory function by determining the conjugation status of the substrate proteins. To target and identify UBL-modifying enzymes, we produced Nedd8, ISG15, and SUMO-1 in Escherichia coli and equipped them with a C-terminal electrophilic trap (vinyl sulfone [VS]) via an intein-based method. These C-terminally modified UBL probes reacted with purified UBL-activating (E1), -conjugating (E2), and -deconjugating enzymes in a covalent fashion. Modified UBLs were radioiodinated and incubated with cell lysates prepared from mouse cell lines and tissues to allow visualization of polypeptides reactive with individual UBL probes. The cell type-and tissue-specific labeling patterns observed for the UBL probes reflect distinct expression profiles of active enzymes, indicating tissuespecific functions of UBLs. We identify Ub C-terminal hydrolase L1 (UCH-L1) and DEN1/NEDP1/SENP8, in addition to UCH-L3, as proteases with specificity for Nedd8. The Ub-specific protease isopeptidase T/USP5 is shown to react with ISG15-VS. Furthermore, we demonstrate that the desumoylation enzyme SuPr-1 can be modified by SUMO-1-VS, a modification that is dependent on the SuPr-1 active-site cysteine. The UBL probes described here will be valuable tools for the further characterization of the enzymatic pathways that govern modification by UBLs.Ubiquitin (Ub) is a conserved 76-amino-acid protein attached posttranslationally to substrate proteins. This conjugation occurs through an isopeptide bond between the C-terminal carboxylate of Ub and the ε-NH 2 of a lysine side chain in the target protein. Conjugation is achieved by the sequential action of an E1 activating enzyme, E2 conjugating enzymes, and E3 ligases (22). The removal of Ub from substrates is carried out by deubiquitinating enzymes. The long-known Ubspecific cysteine protease families of Ub C-terminal hydrolases (UCHs) and Ub-specific processing proteases (UBPs/USPs) were recently joined by a Ub-specific JAMM motif containing metalloprotease and cysteine proteases containing an OTU domain (2,8,13,63,67).Ub-like proteins (UBLs) are a set of small proteins that share with Ub the ability to be conjugated to a lysine residue in a substrate protein (26). Many UBLs are related in sequence to Ub, and a three-dimensional fold similar to that in Ub has been reported for Nedd8 and SUMO (3, 66). The UBLs ISG15 (also called UCRP) and FAT10 resemble two Ub moieties fused in tandem (19, 54). UBLs do not generally appear to be assembled into multimeric chains upon conjugation to substrates, with the possible exception of SUMO-2 and SUMO-3 (62). Like Ub, most UBLs are expressed as inactive precursors, with extensions at the C terminus, which prevent direct conjugation (26) ( Table 1). These precursors must be processed by sp...

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Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog

Cited by 86 publications

References 53 publications

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

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

Specific and Covalent Targeting of Conjugating and Deconjugating Enzymes of Ubiquitin-Like Proteins

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