ABIN-2, of the TPL-2 Signaling Complex, Modulates Mammalian Inflammation

Webb, Louise V.; Ventura, Sónia; Ley, Steven C.

doi:10.1016/j.it.2019.07.001

Cited by 21 publications

(15 citation statements)

References 66 publications

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“…TNIP2, a suppressor of NF-κB, has been shown to protect against excessive inflammatory response. 18 Previously, TNIP2 as an essential protective factor of allergic airway inflammation has been established. Interaction between ABIN-2 and A20 exacerbated house dust mite-induced allergic responses in airway of mice.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Function of TNFAIP3 Interacting Protein 2 Against Oxygen and Glucose Deprivation/Reoxygenation-Induced Injury in Hippocampal Neuronal HT22 Cells Through Regulation of the TLR4/MyD88/NF-κB Pathway

Yan¹,

Chen²,

Zhang³

et al. 2021

NDT

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Background: Tumor necrosis factor-α (TNF-α)-induced protein 3-interacting protein 2 (TNIP2) has been well demonstrated to act as a principal contributor to the development of inflammatory diseases; however, the role of TNIP2 in cerebral ischemic/reperfusion injury has never been studied. Methods: Gene expression was examined by using quantitative real-time polymerase chain reaction and Western blot. The functional role of TNIP2 in oxygen and glucose deprivation/ reoxygenation (OGD/R)-induced neuronal injury was evaluated using cell counting kit-8, terminal deoxynucleotidyl transferase dutp nick end labeling assay and enzyme-linked immunosorbent assay. Commercial kits were applied to evaluate the activity of NF-kappa -B (NF-κB) and caspase-3, as well as the release of lactate dehydrogenase release (LDH). Results: TNIP2 expression was substantially declined in HT22 cells following OGD/R stimulation. TNIP2 overexpression attenuated ODG/R-induced inflammation in HT22 cells, as evidenced by reduced levels of TNF-α, interleukin (IL)-1β, and intercellular cell adhesion molecule-1 (ICAM-1), and increased levels of IL-10. TNIP2 overexpression also reduced activity of NF-κB under ODG/R condition. Meanwhile, OGD/R treatment caused a reduction of cell viability and an elevation of cell apoptosis in HT22 cells, as indicated by the increase in LDH and caspase-3 activity. Whereas, OGD/R-induced HT22 cell injury was mitigated by TNIP2 overexpression in HT22 cells. Besides, we found the involvement of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/NF-κB pathway in the neuroprotective effect of TNIP2 on OGD/R-induced HT22 cell damage. Conclusion: TNIP2 overexpression mitigates OGD/R-induced inflammatory response and apoptosis. Moreover, TLR4/MyD88/NF-κB pathway participates in the protective effect of TNIP2 on OGD/R-induced neuronal damage.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Function of TNFAIP3 Interacting Protein 2 Against Oxygen and Glucose Deprivation/Reoxygenation-Induced Injury in Hippocampal Neuronal HT22 Cells Through Regulation of the TLR4/MyD88/NF-κB Pathway

Yan¹,

Chen²,

Zhang³

et al. 2021

NDT

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“…ABIN2 was initially identified as a downstream effector of A20, which exerts an NF-κB inhibitory function by interacting with IKK complex adaptor protein NEMO (IKKγ) and phosphorylated tyrosine kinase Tie2 through its ubiquitin-binding in ABIN and NEMO (UBAN) domain 105 , 106 . Consequently, ABIN2 dysregulation results in increased inflammation and tumorigenesis in an NF-κB-dependent manner 107 . Given that NF-κB1 p105 and TPL2 protein stabilize ABIN2, and the TPL2 kinase activity regulates ABIN2 gene expression, depletion of either TPL2 or NF-κB1 p105 can result in the suppressed expression of ABIN2 43 , 108 .…”

Section: Tpl2 and Its Adaptor Functionmentioning

confidence: 99%

“…The study proposed that the TPL2 kinase activity was responsible for coordinating fibroblast response to injury and governing epithelial tissue homeostasis through the regulation of basement membrane integrity and wound healing 111 . However, the real culprit was provided by a study using mice expressing ABIN2 [D310N], an ABIN2 containing a mutation on the UBAN domain that binds to linear and K63-linked polyubiquitin chains 107 , 112 . ABIN2 [D310N] mice displayed intestinal inflammation and hypersensitivity to chemical-induced colitis, similar to the TPL2 deficient mice phenotype 111 , 112 .…”

Section: Tpl2 and Its Adaptor Functionmentioning

confidence: 99%

“…However, given that TPL2 kinase is a positive regulator of IL-10 expression, it is also possible that loss of TPL2 activity impairs IL-10-mediated anti-inflammatory signaling, resulting in the subsequent increase of intestinal inflammation that drives tumorigenesis 92 . The ABIN2 function in tissue homeostasis and anti-inflammatory responses underscore its importance in inflammation, and these functions should be considered when making phenotypic assumptions in TPL2 ablation studies 107 , 108 . Unfortunately, it is yet to be determined whether the identified function of ABIN2 in inflammation translates to tumorigenesis, especially in tumors expressing suppressed levels of TPL2.…”

Section: Tpl2 and Its Adaptor Functionmentioning

confidence: 99%

“…While most evidence supports the oncogenic function of TPL2, several studies have proposed the anti-inflammatory and anti-tumorigenic role of TPL2 signaling. A plausible explanation to this paradox is that in addition to its TPL2 kinase activity, the adaptor function of the TPL2 protein plays an essential role in modulating tissue homeostasis, inflammation and tumorigenesis 107 . It would be beneficial to investigate whether ABIN2 and NF-κB1 p105 signaling contribute to the increased NF-κB signaling, COX2 production, and the subsequent activation of the HGF/c-Met signaling in the absence of TPL2.…”

Section: Perspective and Conclusionmentioning

confidence: 99%

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Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Njunge¹,

Estania²,

Guo³

et al. 2020

Theranostics

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Over the years, tumor progression locus 2 (TPL2) has been identified as an essential modulator of immune responses that conveys inflammatory signals to downstream effectors, subsequently modulating the generation and function of inflammatory cells. TPL2 is also differentially expressed and activated in several cancers, where it is associated with increased inflammation, malignant transformation, angiogenesis, metastasis, poor prognosis and therapy resistance. However, the relationship between TPL2-driven inflammation, tumorigenesis and tumor immunity has not been addressed. Here, we reconcile the function of TPL2-driven inflammation to oncogenic functions such as inflammation, proliferation, apoptosis resistance, angiogenesis, metastasis, immunosuppression and immune evasion. We also address the controversies reported on TPL2 function in tumor-promoting inflammation and tumorigenesis, and highlight the potential role of the TPL2 adaptor function in regulating the mechanisms leading to pro-tumorigenic inflammation and tumor progression. We discuss the therapeutic implications and limitations of targeting TPL2 for cancer treatment. The ideas presented here provide some new insight into cancer pathophysiology that might contribute to the development of more integrative and specific anti-inflammatory and anti-cancer therapeutics.

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Differential involvement of LUBAC‐mediated linear ubiquitination in intestinal epithelial cells and macrophages during intestinal inflammation

Sakamoto

Sasaki

Omatsu

et al. 2022

The Journal of Pathology

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Disruption of the intestinal epithelial barrier and dysregulation of macrophages are major factors contributing to the pathogenesis of inflammatory bowel diseases (IBDs). Activation of NF-κB and cell death are involved in maintaining intestinal homeostasis in a cell type-dependent manner. Although both are regulated by linear ubiquitin chain assembly complex (LUBAC)-mediated linear ubiquitination, the physiological relevance of linear ubiquitination to intestinal inflammation remains unexplored. Here, we used two experimental mouse models of IBD (intraperitoneal LPS and oral dextran sodium sulfate [DSS] administration) to examine the role of linear ubiquitination in intestinal epithelial cells (IECs) and macrophages during intestinal inflammation. We did this by deleting the linear ubiquitination activity of LUBAC specifically from IECs or macrophages. Upon LPS administration, loss of ligase activity in IECs induced mucosal inflammation and augmented IEC death. LPS-mediated death of LUBAC-defective IECs was triggered by TNF. IEC death was rescued by an anti-TNF antibody, and TNF (but not LPS) induced apoptosis of organoids derived from LUBAC-defective IECs. However, augmented TNF-mediated IEC death did not overtly affect the severity of colitis after DSS administration. By contrast, defective LUBAC ligase activity in macrophages ameliorated DSS-induced colitis by attenuating both infiltration of macrophages and expression of inflammatory cytokines. Decreased production of macrophage chemoattractant MCP-1/CCL2, as well as pro-inflammatory IL-6 and TNF, occurred through impaired activation of NF-κB and ERK via loss of ligase activity in macrophages. Taken together, these results indicate that both intraperitoneal LPS and oral DSS administrations are beneficial for evaluating epithelial integrity under inflammatory conditions, as well as macrophage functions in the event of an epithelial barrier breach. The data clarify the cell-specific roles of linear ubiquitination as a critical regulator of TNF-mediated epithelial integrity and macrophage pro-inflammatory responses during intestinal inflammation.

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ABIN-2, of the TPL-2 Signaling Complex, Modulates Mammalian Inflammation

Cited by 21 publications

References 66 publications

Neuroprotective Function of TNFAIP3 Interacting Protein 2 Against Oxygen and Glucose Deprivation/Reoxygenation-Induced Injury in Hippocampal Neuronal HT22 Cells Through Regulation of the TLR4/MyD88/NF-κB Pathway

Neuroprotective Function of TNFAIP3 Interacting Protein 2 Against Oxygen and Glucose Deprivation/Reoxygenation-Induced Injury in Hippocampal Neuronal HT22 Cells Through Regulation of the TLR4/MyD88/NF-κB Pathway

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Differential involvement of LUBAC‐mediated linear ubiquitination in intestinal epithelial cells and macrophages during intestinal inflammation

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