Smurf1 Protein Negatively Regulates Interferon-γ Signaling through Promoting STAT1 Protein Ubiquitination and Degradation

Yuan, Chao; Qi, Jianni; Zhao, Xueying; Gao, Chengjiang

doi:10.1074/jbc.m112.341198

Cited by 64 publications

(49 citation statements)

References 32 publications

(38 reference statements)

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“…STAT1 plays a critical role in IFNγ signal transduction and is a target for ubiquitin ligases [16–18]. Therefore, we next examined the possibility that NKLAM and STAT1 associate physically.…”

Section: Resultsmentioning

confidence: 99%

“…Nuclear E3 ubiquitin ligase STAT–interacting LIM protein (SLIM), ubiquitinates STAT1 and STAT4, causing their degradation in vitro and in vivo [17]. Similarly, E3 ligase Smad ubiquitination regulation factor 1 (Smurf1) was shown to bind a PY domain in STAT1 via a WW domain in Smurf1 and facilitate ST AT1 proteasomal degradation [18]. Additionally, Sendai virus C proteins monoubiquitinate STAT1 causing its degradation in order to circumvent the innate immune response [19].…”

Section: Introductionmentioning

confidence: 99%

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E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity

Lawrence

Kornbluth

2016

Cellular Signalling

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Signal transducer and activator of transcription 1 (STAT1) is critically important for the transcription of a large number of immunologically relevant genes. In macrophages, interferon gamma (IFNγ) signal transduction occurs via the JAK/STAT pathway and ends with the transcription of a number of genes necessary for a successful host immune response. The predominant mechanism of regulation of STAT1 is phosphorylation; however, there is a growing body of evidence that demonstrates STAT1 is also regulated by ubiquitination. In this report we show that JAK1 and STAT1 in macrophages deficient in an E3 ubiquitin ligase termed Natural Killer Lytic-Associated Molecule (NKLAM) are hyperphosphorylated following IFNγ stimulation. We found NKLAM was transiently localized to the IFNγ receptor complex during stimulation with IFNγ, where it bound to and mediated K63-linked ubiquitination of STAT1. In vitro nucleofection studies demonstrated that STAT1-mediated transcription was significantly reduced in NKLAM-KO macrophages. There was no obvious defect in STAT1 nuclear translocation; however, STAT1 from NKLAM-KO macrophages had a reduced ability to bind a functional gamma activation DNA sequence. There was also less mRNA expression of STAT1-mediated genes in NKLAM-KO macrophages treated with IFNγ. Our results demonstrate for the first time that NKLAM is a positive regulator of STAT1-mediated transcriptional activity and is an important component of the innate immune response.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity

Lawrence

Kornbluth

2016

Cellular Signalling

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“…Low or defective TAP1 in breast tumors predicts higher risks for developing metastasis [35] and down-regulation of the interferon-stimulated genes IFIT1 and MX1 has been linked to immune evasion mechanisms and tumor progression [36-39]. Interestingly, E3 ligases are involved in the efficient regulation of the immune system [40-42] and alterations in the ubiquitination machinery/pathway are associated with immune deficiencies and cancer [43]. …”

Section: Discussionmentioning

confidence: 99%

CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response

et al. 2014

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The CUL4A E3 ubiquitin ligase is involved in the regulation of many cellular processes and its amplification and/or overexpression has been observed in breast cancer. The 13q34 amplification, which is associated with the basal-like breast cancer subtype, has been proposed as one of the mechanism behind CUL4A up-regulation. However, the specific contribution of CUL4A to the biology of basal-like breast tumors has not yet been elucidated. In this work, by using cellular models of basal phenotype, we show the inhibitory effect of CUL4A silencing in the proliferation and growth of breast cancer cells both, in vitro and in vivo. We also demonstrate the transforming capacity of CUL4A exogenous overexpression in the 184B5 human mammary epithelial cells in vitro. Our results suggest a synergistic effect between CUL4A high levels and the activation of the RAS pathway in the tumorigenesis of basal-like breast cancer tumors. In addition, by using a proteomics approach we have defined novel candidate proteins and pathways that might mediate the oncogenic effect of CUL4A. In particular, we report a putative role of CUL4A in bypassing the immune system in breast cancer through the down-regulation of several molecules involved in the immune surveillance. These findings provide insight into the oncogenic properties of CUL4A in basal-like breast cancer and highlight the therapeutic opportunities to target CUL4A.

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“…Kim and Maniatis reported that STAT1 becomes ubiquitinylated after IFNγ stimulation [18]. Other studies also show that STAT1 can be ubiquitinylated and degraded by the proteasome to restrict IFN-dependent JAK-STAT signaling [19, 20]. Remarkably, some pathogens like the SV5 or Mumps virus inactivate STAT1 via the induction of its proteasomal degradation [21, 22].…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 and Caspase-6 cleave STAT1 in leukemic cells

et al. 2014

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Signal Transducer and Activator of Transcription-1 (STAT1) is phosphorylated upon interferon (IFN) stimulation, which can restrict cell proliferation and survival. Nevertheless, in some cancers STAT1 can act in an anti-apoptotic manner. Moreover, certain malignancies are characterized by the overexpression and constitutive activation of STAT1. Here, we demonstrate that the treatment of transformed hematopoietic cells with epigenetic drugs belonging to the class of histone deacetylase inhibitors (HDACi) leads to the cleavage of STAT1 at multiple sites by caspase-3 and caspase-6. This process does not occur in solid tumor cells, normal hematopoietic cells, and leukemic cells that underwent granulocytic or monocytic differentiation. STAT1 cleavage was studied under cell free conditions with purified STAT1 and a set of candidate caspases as well as with mass spectrometry. These assays indicate that unmodified STAT1 is cleaved at multiple sites by caspase-3 and caspase-6. Our study shows that STAT1 is targeted by caspases in malignant undifferentiated hematopoietic cells. This observation may provide an explanation for the selective toxicity of HDACi against rapidly proliferating leukemic cells.

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Smurf1 Protein Negatively Regulates Interferon-γ Signaling through Promoting STAT1 Protein Ubiquitination and Degradation

Cited by 64 publications

References 32 publications

E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity

E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity

CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response

Caspase-3 and Caspase-6 cleave STAT1 in leukemic cells

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