RIPK1-TRAF2 interplay on the TNF/NF-κB signaling, cell death, and cancer development in the liver

Yamamoto, Saburo; Iwakuma, Tomoo

doi:10.21037/tcr.2017.04.01

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…However, further studies are needed to clarify the exact effect of RIPK1 on the pathogenesis of OA. Moreover, TRAF2 interacts with RIPK1 directly via its N-terminus [18, 19]. TRAF2 plays an important role in alleviating apoptosis and inflammation [20], and knockout of TRAF2 triggers apoptosis and inflammation by an NF-κB–independent mechanism [21].…”

Section: Introductionmentioning

confidence: 99%

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

Liang

Wang

Zhang

et al. 2019

Aging

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Osteoarthritis (OA) is the most common degenerative joint disease and involves the loss of articular cartilage integrity, formation of articular osteophytes, remodeling of subchondral bone, and synovitis. Knockdown of receptor interacting serine/threonine kinase (RIPK) 1 leads to anti-inflammatory and anti-apoptotic effects. However, the involvement of RIPK1 in the pathogenesis of OA is unclear. Here, we evaluated the effect of RIPK1 on chondrocytes and elaborated the underlying molecular mechanism. Knockdown of RIPK1 protected chondrocytes against inflammation and apoptosis induced by interleukin (IL)-1β in vitro and in vivo. RIPK1 was required for myeloid differentiation primary response 88 (MyD88)- and TIR-domain-containing adapter-inducing interferon b (TRIF)-mediated production of matrix metalloproteinases (MMPs) in OA. Moreover, overexpression of RIPK1 promoted the expression of tumor necrosis factor receptor-associated factor 2 (TRAF2), which blocked the expression and phosphorylation of RIPK1. Upregulation of TRAF2 decreased the expression of TRIF, MyD88, and MMPs in chondrocytes. Furthermore, knockdown of RIPK1 blocked activation of the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. In summary, knockdown of RIPK1 alleviated OA in a manner mediated by the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop and activation of the NF-κB and JNK signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

Liang

Wang

Zhang

et al. 2019

Aging

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“…RIPK1 seems to act as a bridge between stress and the immune response also through its interactions with CD14 (Monocyte differentiation antigen CD14 (Cd14) that mediates the immune response to bacterial LPS), MAP2K3 (which is activated by cytokines and environmental stress processes), STAT1 (Signal transducer and activator of transcription 1 (Stat1) which modulates responses to many cytokines and interferons 84 ) and IFIH1 (Interferon-induced helicase C domain-containing protein 1 (Ifih1) that acts as a viral sensor and plays a major role in the activation of the antiviral response through an increase in pro-inflammatory cytokines and type I interferons 85 ) from clusters 1 and 2 (Figure 5 and S6). This points RIPK1 as a strong candidate to mediate BiP signal transduction in the cell surface of neutrophils and alveolar macrophages while acting as a co-receptor of NFKB/TNF signals 86, 87 . Recently, RIPK1 activation was described in human COVID-19 lung samples; inhibition of RIPK1 with the use of small molecules reduced lung viral load and mortality in ACE2 transgenic mice 69, 88 .…”

Section: Discussionmentioning

confidence: 99%

Cellular stress modulates severity of the acute respiratory distress syndrome in COVID-19

Rico-Llanos

Porras

Escalante

et al. 2022

Preprint

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Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we demonstrate that cell surface BiP (cs-BiP) responds by increasing its levels in leukocytes. Neutrophiles show the highest levels of cs-BiP and respond by increasing their population, whereas alveolar macrophages increase their levels of cs-BiP. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.

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“…Receptor-interacting serine/threonine-protein kinase 1(RIPK1), a core component (scaffold function) of (tumor necrosis factor receptor 1) TNFR1 complex, serves as a vital cellular signaling hub that participates in TNF-mediated apoptosis and inflammatory pathways [ 5 , 6 ]. Also, RIPK1 directly interacts with RIPK3 to promote the activation of necroptosis in a kinase activity-dependent manner [ 7 ]. In mouse models, RIPK1 depletion leads to multi-organ inflammation and abnormal cell death in animals [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The vital functions of RIPK1 have been extensively investigated in solid tumors, such as hepatocellular carcinoma, soft-tissue sarcoma, melanoma, cervical Cancer, etc. [ 7 , 15 – 17 ] However, whether and how RIPK1 is implicated in hematological malignancies (especially B-cell cancers) is still not fully explored.…”

Section: Introductionmentioning

confidence: 99%

RIPK1 is aberrantly expressed in multiple B-cell cancers and implicated in the underlying pathogenesis

Wu¹,

Li²,

Wang³

et al. 2023

Discov Onc

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According to the latest epidemiology of the US, B-cell cancers account for > 3% of all new cancer cases and > 80% of non-Hodgkin lymphomas. However, the disease-modifying small molecular drug suitable for most B-cell cancers is still lacking. RIPK1 (receptor-interacting serine/threonine-protein kinase 1) has been observed to be dysregulated and implicated in the pathogenesis of multiple solid cancers, of which, however, the roles in blood cancers are quite unclear. In our study, to identify multi-function targets for B-cell cancer treatment, we reanalyzed a public transcriptomic dataset from the database of Gene Expression Omnibus, which includes CD19+ B-cell populations from 6 normal donors and patients of 5 CLL, 10 FL, and 8 DLBCL. After overlapping three groups (CLL vs. normal, FL vs. normal, and DLBCL vs. normal) of differentially expressed genes (DEGs), we obtained 69 common DEGs, of which 3 were validated by real-time quantitative PCR, including RIPK3, IGSF3, TGFBI. Interestingly, we found that the loss function of RIPK1 significantly increases the proliferation and viability of GM12878 cells (a normal human B lymphocyte cell line). Consistently, overexpression of RIPK1 in TMD8 and U2932 cells effectively inhibited cell proliferation and growth. More importantly, modifying RIPK1 kinase activity by a small molecule (such as necrostain-1, HOIPIN-1, etc.) alters the cell growth status of B-cell lymphoma, showing that RIPK1 exhibits anti-tumor activity in the context of B-cell lymphoma. Taken together, we consider that RIPK1 may be a potential target in the clinical application of B-cell lymphoma (including CLL, DLBCL, and FL) treatment.

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RIPK1-TRAF2 interplay on the TNF/NF-κB signaling, cell death, and cancer development in the liver

Cited by 6 publications

References 19 publications

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

Cellular stress modulates severity of the acute respiratory distress syndrome in COVID-19

RIPK1 is aberrantly expressed in multiple B-cell cancers and implicated in the underlying pathogenesis

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