HSCARG downregulates NF-κB signaling by interacting with USP7 and inhibiting NEMO ubiquitination

Li, T; Guan, Jialiang; Li, S; Zhang, X; Zheng, Xiaofeng

doi:10.1038/cddis.2014.197

Cited by 32 publications

(30 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…USP7 can also interact with other viral proteins, such as the EBNA1 protein of the Epstein-Barr virus (EBV) [80] and the Viral Interferon Regulatory Factor 1 (vIRF1) of a Kaposi sarcoma herpesvirus protein [81]. In addition, and as mentioned before, USP7 plays a role by regulating NF- κ B signalling [24, 25]. Unfortunately USP7 −/− mice are embryonically lethal explaining the lack of in vivo studies to further characterize the role of USP7 in immune responses and associated pathologies [82].…”

Section: Deubiquitinases and Inflammatory Diseasementioning

confidence: 99%

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

López-Castejón

Edelmann

2016

Mediators of Inflammation

View full text Add to dashboard Cite

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies.

show abstract

Section: Deubiquitinases and Inflammatory Diseasementioning

confidence: 99%

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

López-Castejón

Edelmann

2016

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…More recently, USP7 was reported to regulate NF‐κB transcriptional activity in the nucleus, by increasing NF‐κB stability . However, similar to A20 and CYLD, cytosolic USP7 can also act as a negative regulator of the NF‐κB pathway by mediating the deubiquitination of NEMO that leads to the retention of NF‐κB in the cytosol, thus suppressing its activity . These reported roles suggest that USP7 activity can perform opposing functions, depending on cellular localisation and substrate recognition, although how this is achieved is unclear.…”

Section: Introductionmentioning

confidence: 99%

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

et al. 2018

View full text Add to dashboard Cite

The assembly and activation of the inflammasomes are tightly regulated by post‐translational modifications, including ubiquitin. Deubiquitinases (DUBs) counteract the addition of ubiquitin and are essential regulators of immune signalling pathways, including those acting on the inflammasome. How DUBs control the assembly and activation of inflammasomes is unclear. Here, we show that the DUBs USP7 and USP47 regulate inflammasome activation in macrophages. Chemical inhibition of USP7 and USP47 blocks inflammasome formation, independently of transcription, by preventing ASC oligomerisation and speck formation. We also provide evidence that the ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. Interestingly, we found that the activity of USP7 and USP47 increased in response to inflammasome activators. Using CRISPR/Cas9 in the macrophage cell line THP‐1, we show that inflammasome activation is reduced when both USP7 and USP47 are knocked down. Altogether, these data reveal a new post‐transcriptional role for USP47 and USP7 in inflammation by regulating inflammasome activation and the release of the pro‐inflammatory cytokines IL‐1β and IL‐18, and implicate dual USP7 and USP47 inhibitors as potential therapeutic agents for inflammatory disease.

show abstract

“…To ensure that immune response is tightly controlled, ubiquitination functions as an effective regulatory mechanism where ubiquitin molecules are conjugated to diverse target proteins and affect the stability or activity of these proteins [1]. For example, in NF-κB signaling pathway of innate immunity, TRAF6-mediated K63 poly-ubiquitin chain activates IKK complex for phosphorylation, which subsequently promotes poly-ubiquitination of IκBα and leads to its degradation, thereby releasing NF-κB for transcription activation [5,6,7]. As ubiquitin system is largely involved in the immune signaling, its regulatory roles in various signal transduction processes need further exploration.…”

Section: Introductionmentioning

confidence: 99%

MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination

Yan

Guan

Peng

et al. 2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Myeloid differentiation factor 88 (MyD88) plays a central role in innate immunity response, however, how its activity is tightly regulated remains largely unknown. In this study, we identify MyD88 as a novel substrate of NEDD8, and demonstrate that MyD88 NEDDylation antagonizes its ubiquitination. Interestingly, in response to the stimulation of IL-1β, MyD88 NEDDylation is downregulated while its ubiquitination is upregulated. We also show that deNEDDylase NEDP1 serves as a regulator of this process. Furthermore, we demonstrate that NEDD8 negatively regulates the dimerization of MyD88 and suppresses MyD88-dependent NF-κB signaling. Taken together, this study reveals that NEDDylation of MyD88 regulates NF-κB activity through antagonizing its ubiquitination, suggesting a novel mechanism of modulating NF-κB signaling pathway.

show abstract

HSCARG downregulates NF-κB signaling by interacting with USP7 and inhibiting NEMO ubiquitination

Cited by 32 publications

References 41 publications

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation

MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination

Contact Info

Product

Resources

About