A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Proteins selected for degradation are labeled with multiple molecules of ubiquitin and are subsequently cleaved by the 26 S proteasome. A family of proteins containing at least one ubiquitinassociated (UBA) domain and one ubiquitin-like (UBL) domain have been shown to act as soluble ubiquitin receptors of the 26 S proteasome and introduce a new level of specificity into the degradation system. They bind ubiquitylated proteins via their UBA domains and the 26 S proteasome via their UBL domain and facilitate the contact between substrate and protease. NEDD8 ultimate buster-1 long (NUB1L) belongs to this class of proteins and contains one UBL and three UBA domains. We recently reported that NUB1L interacts with the ubiquitin-like modifier FAT10 and accelerates its degradation and that of its conjugates. Here we show that a deletion mutant of NUB1L lacking the UBL domain is still able to bind FAT10 but not the proteasome and no longer accelerates FAT10 degradation. A version of NUB1L lacking all three UBA domains, on the other hand, looses the ability to bind FAT10 but is still able to interact with the proteasome and accelerates the degradation of FAT10. The degradation of a FAT10 mutant containing only the C-terminal UBL domain is also still accelerated by NUB1L, even though the two proteins do not interact. In addition, we show that FAT10 and either one of its UBL domains alone can interact directly with the 26 S proteasome. We propose that NUB1L not only acts as a linker between the 26 S proteasome and ubiquitinlike proteins, but also as a facilitator of proteasomal degradation.Ubiquitin, a small protein of 76 amino acids is one of the most conserved proteins known and has been found in all eukaryotic cells studied. It is essential for a variety of cellular processes, including degradation, cell-cycle regulation, DNA repair, stress response, embryogenesis, apoptosis, signal transduction, and transmembrane and vesicular transport (1-6). Throughout the past years, a family of proteins containing structural motives related to ubiquitin has been described that can be grouped into the ubiquitin-like modifiers and the ubiquitin-domain proteins (7). The ubiquitin-like modifiers have substantial sequence or structural homology to ubiquitin and form covalent conjugates with their target proteins. However, unlike ubiquitin, which can form large polymeric conjugates, usually only monomeric modifications are observed. As is the case for ubiquitin, a C-terminal diglycine motif is essential for conjugation of most modifiers to their target proteins (8). Prominent members of this group include SUMO-1, which serves several functions including nuclear transport and budding (9, 10), NEDD8, which regulates SCF ubiquitin-ligases via cullin modification (11), ISG15, which plays a role in innate immunity and in the response to ␣-interferon (12, 13), and FAT10, which is inducible with ␥-interferon (IFN)-␥ 4 and tumor necrosis factor ␣ (TNF-␣) (14, 15), and has been shown to cause apoptosis upon ectopic expression (16).The ubiquitin-li...

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“…Purification of 26 S Proteasomes-Purification of 26 S proteasomes was performed as detailed elsewhere (41).…”

Section: Methodsmentioning

confidence: 99%

The UBA Domains of NUB1L Are Required for Binding but Not for Accelerated Degradation of the Ubiquitin-like Modifier FAT10

Schmidtke

Kalveram

Weber

et al. 2006

Journal of Biological Chemistry

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“…27 In addition, both HCMV and murine cytomegalovirus (MCMV) do not alter the constitutive subunit composition of the proteasome in infected cells, but block the immunoproteasome formation; as a result, the shaping of the CD8 1 T-cell response is affected. 28 …”

Section: Impaired Cleavage Function Of Proteasomementioning

confidence: 99%

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

Seliger

Ritz

Ferrone

2005

Intl Journal of Cancer

112

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In humans as in other animal species, CD81 cytotoxic T lymphocytes (CTLs) play an important if not the major role in controlling virus-infected and malignant cell growth. The interactions between CD81 T cells and target cells are mediated by human leukocyte antigen (HLA) class I antigens loaded with viral and tumor antigen-derived peptides along with costimulatory receptor/ligand stimuli. Thus, to escape from CD8 1 T-cell recognition and destruction, viruses and tumor cells have developed strategies to inhibit the expression and/or function of HLA class I antigens. In contrast, cells with downregulated MHC class I surface expression can be recognized by NK cells, although NK cell-mediated lysis could be abrogated by the expression of inhibiting NK cell receptors. This review discusses the molecular mechanisms utilized by viruses to inhibit the formation, transport and/or expression of HLA class I antigen/peptide complexes on the cell surface. The knowledge about viral interference with MHC class I antigen presentation is not only crucial to understand the pathogenesis of viral diseases, but contributes also to the design of novel strategies to counteract the escape mechanisms utilized by viruses. These investigations may eventually lead to the development of effective immunotherapies to control viral infections and virus-associated malignant diseases. ' 2005 Wiley-Liss, Inc.

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“…For cytomegaloviruses (CMV), a number of genes were reported to code for inhibitors counteracting IFN responses. The mouse cytomegalovirus (MCMV) M27 protein downregulates STAT2 to disrupt IFN-a/b and IFN-c signal transduction, resulting in a dramatic attenuation of viral replication in vivo (Khan et al, 2004;Zimmermann et al, 2005). The human CMV (HCMV) immediate-early 1 (ie1)-encoded protein pp72 was described as a STAT-interacting protein that diminishes ISGF3-dependent transcription (Paulus et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Trilling

Zimmermann

et al. 2008

Journal of General Virology

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We have investigated beta interferon (IFN-b) and IFN-a4 gene expression and activation of related transcription factors in mouse cytomegalovirus (MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN gene induction upon MCMV infection, which was followed by a sustained MCMV-mediated simultaneous downregulation of IFN-b and IFN-a4 gene expression. The induction of IFN transcription resulted from the activation of the components of the IFN-b enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-kB, activating transcription factor (ATF)-2 and c-Jun. Activation of the transcription factors occurred rapidly and in a sequential order upon infection, but only lasted a while. As a consequence, IFN-a/b gene expression became undetectable 6 h post-infection and throughout the MCMV replication cycle. This effect is based on an active interference since restimulation of IFN gene induction by further external stimuli (e.g. Sendai virus infection) was completely abolished. This inhibition required MCMV gene expression and was not observed in cells infected with UV-inactivated MCMV virions. The efficiency of inhibition is achieved by a concerted blockade of IkBa degradation and a lack of nuclear accumulation of IRF3 and ATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and activator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, we found that the initial phase of IFN induction and the subsequent inhibition does not depend on the positive-IFN feedback loop. Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex. INTRODUCTIONUpon virus infection the type I interferon (IFN-a/b) response is one of the earliest innate host defence mechanisms, and many viruses have found means to avoid IFN gene expression Haller et al., 2006). Production of IFN-a/b is induced by the recognition of pathogen-associated molecular patterns (PAMP) (Medzhitov & Janeway, 2002) and initiates transcriptional upregulation of IFN-stimulated genes (ISGs) to establish an antiviral state. IFN-a/b synthesized by virus-infected cells bind to the IFN-a/b receptor complex, termed IFNAR, and activates the Jak/STAT signal transduction cascade, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3). ISGF3 binds to IFN-stimulated response elements (ISRE), located in the promoter region of IFNinducible target genes mediating IFN effector functions (Darnell et al., 1994).Initiation of IFN transcription and its subsequent autocrine and paracrine amplification is a prerequisite for efficient IFN effector responses. IFN-b gene transcription is controlled by a higher order transcription enhancer complex, known as enhanceosome (Maniatis, 1986;Maniatis et al., 1998). The multi-component complex includes three distinct transcription factors binding cooperatively to the IFN-b promoter and the architectural high mobili...

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A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Cited by 62 publications

References 70 publications

The UBA Domains of NUB1L Are Required for Binding but Not for Accelerated Degradation of the Ubiquitin-like Modifier FAT10

The UBA Domains of NUB1L Are Required for Binding but Not for Accelerated Degradation of the Ubiquitin-like Modifier FAT10

Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

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