SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses

Mathewson, Nathan D.; Fujiwara, Hideaki; Wu, Shenghao; Toubai, Tomomi; Oravecz-Wilson, Katherine; Sun, Yaping; Rossi, Corinne; Zajac, Cynthia; Sun, Yi; Reddy, Pavan

doi:10.1016/j.ajpath.2016.06.014

Cited by 26 publications

(25 citation statements)

References 34 publications

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“…IFN-γ, IL-2 and IL-4), which is required for efficient Th1 and Th2 differentiation [70], demonstrating a potent positive function of neddylation pathway in T-cell activation [69, 71]. Consistently, deletion of RBX2 significantly decreased T-cell activation and T-effector cytokine release upon in vitro allogeneic stimulation [72].…”

Section: Introductionmentioning

confidence: 99%

Neddylation: a novel modulator of the tumor microenvironment

et al. 2019

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Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.

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Section: Introductionmentioning

confidence: 99%

Neddylation: a novel modulator of the tumor microenvironment

et al. 2019

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“…More specifically, previous studies (both ours and others) have shown that SAG and SAG-dependent neddylation play a critical role in regulation of the inflammatory response involving several immune cells, including macrophages (9), dendritic cells (16), and T-cells (30), and interestingly, in human hepatocellular carcinoma cells as well (31, 32). Specifically, inactivation of Sag by siRNA-mediated knockdown or chemical inhibition of neddylation with MLN4924, a potent small molecular inhibitor of NEDD8 activating enzyme E1 NAE that effectively blocks cullin neddylation to inhibit CRL activation (33), impaired inflammatory response.…”

Section: Discussionmentioning

confidence: 59%

SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets

Xiong

Mathewson

et al. 2018

Front. Immunol.

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Macrophages form an important component of the innate immune system and serve as first responders against invading pathogens. While pathways critical for initiation of inflammatory responses between macrophages and other LysM+ myeloid cells are largely similar, it remains unknown whether a specific pathway has differential effects on inflammatory responses mediated between these cells. Recent studies demonstrated that depletion of SAG (Sensitive to Apoptosis Gene), an E3 ubiquitin ligase, blocked inflammatory responses generated by macrophages and dendritic cells in response to LPS in cell culture settings. However, the in vivo role of Sag on modulation of macrophages and neutrophil is not known. Here we generated LysM-Cre/Sagfl/fl mice with selective Sag deletion in myeloid lineage, and found that in contrast to in vitro observations, LysM-Cre/Sagfl/fl mice showed increased serum levels of proinflammatory cytokines and enhanced mortality in response to LPS. Interestingly, while Sag−/− macrophages released less proinflammatory cytokines, Sag−/− neutrophils released more. Mechanistically, expression of a list of genes response to LPS was significantly altered in bone marrow cells from LysM-Cre+/Sagfl/fl mice after LPS challenge. Specifically, induction by LPS of myeloperoxidase (Mpo), a key neutrophil enzyme, and Elane, neutrophil expressed elastase, was significantly decreased upon Sag depletion. Collectively, our study revealed that Sag plays a differential role in the activation of macrophages and neutrophils.

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“…Besides, further research reveals that the sensitive to apoptosis gene (SAG), a neddylation E3 ligase, collaborates with UPS to promote survival of infectious macrophages via degrading proapoptotic Bax and sterile α and HEAT/armadillo-motif-containing protein (SARM) (112). SAG also affects cytokine secretion of macrophages (113). Similar to innate immune cells, SAG-deficient T cells also show decreased proliferation, reduced production of cytokines, and diminished release of the T-cell lineage.…”

Section: Neddylation and Hccmentioning

confidence: 99%

“…Similar to innate immune cells, SAG-deficient T cells also show decreased proliferation, reduced production of cytokines, and diminished release of the T-cell lineage. Besides, knockdown of Ubc12 in CD4+ T cells caused impaired T-cell receptor/CD28-induced proliferation because T cells were arrested in the G0/G1 phase of the cell cycle (113). Moreover, cytokine production like IL-2 and the differentiation of CD4+ T cells into effector Thcell subsets are decreased when the expression of Ubc12 is reduced.…”

Section: Neddylation and Hccmentioning

confidence: 99%

Neddylation: A Versatile Pathway Takes on Chronic Liver Diseases

et al. 2020

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Neddylation is a ubiquitin-like posttranslational modification that conjugates neural precursor cell expressed developmentally downregulated-8 (Nedd8) to specific substrates for regulation of protein activity. In light of current researches, the neddylation pathway is aberrant in the pathogenesis of many diseases. In our review, we summarize the versatile roles of neddylation in chronic liver diseases (CLDs). CLDs are one of the leading causes of chronic disease-associated deaths worldwide. There are diverse etiologic agents causing CLDs, mainly including hepatitis B virus (HBV) infection, nonalcoholic fatty liver disease (NAFLD), chronic exposure to alcohol or drugs, and autoimmune causes. So far, however, there remains a paucity of effective therapeutic approach to CLDs. In this review, we summarized the role of the neddylation pathway which runs through the chronic hepatitis B/NAFLD-liver fibrosis-cirrhosis-hepatocellular carcinoma (HCC) axis, a canonical pattern in the process of CLD development and progression. The dysregulation of neddylation may provide a better understanding of CLD pathology and even a novel therapeutic strategy. Correspondingly, inhibiting neddylation via MLN4924, a small molecule compound targeting NEDD8-activating enzyme (NAE), can potently alleviate CLD progression and improve the outcome. On this basis, profiling and characterization of the neddylation pathway can provide new insights into the CLD pathology as well as novel therapeutic strategies, independently of the etiology of CLD.

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SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses

Cited by 26 publications

References 34 publications

Neddylation: a novel modulator of the tumor microenvironment

Neddylation: a novel modulator of the tumor microenvironment

SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets

Neddylation: A Versatile Pathway Takes on Chronic Liver Diseases

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