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Background Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. Methods RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. Results We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. Conclusions Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.

Background Angiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). According to previous studies, miR-378a participates in tumorigenesis and tumor metastasis, but its exact role in HCC angiogenesis remains poorly understood. Methods qRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by Cell Counting Kit-8 (CCK-8), Transwell, tube formation and Matrigel plug assays, RNA sequencing, bioinformatics, luciferase reporter, immunofluorescence and chromatin immunoprecipitation (ChIP) assays were used to detect the molecular mechanism by which miR-378a-3p inhibits angiogenesis. Results We confirmed that miR-378a-3p expression was significantly downregulated and associated with higher microvascular density (MVD) in HCC; miR-378a-3p downregulation indicated a short survival time in HCC patients. miR-378a-3p knockdown led to a significant increase in angiogenesis in vitro and in vivo. We found that miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then downregulated secreted vascular endothelial growth factor. DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of miR-378a-3p was responsible for downregulating miR-378a-3p. Moreover, a series of investigations indicated that p65 initiated a positive feedback loop that could upregulate DNMT1 to promote hypermethylation of the miR-378a-3p promoter. Conclusion Our study indicates a novel DNMT1/miR-378a-3p/TRAF1/NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.

CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.

Background Helicobacter pylori (Hp) infection is the primary cause of gastric cancer. We previously demonstrated that TRAF1 expression was significantly increased during the multistep pathological timeline of Correa’s cascade and that these changes were closely correlated with Hp virulence factor VacA. However, the underlying mechanism remains unknown. Methods TRAF1-deficient or overexpressing human gastric mucosal epithelial cells were generated, and wild-type/ vacA -KO mutant Hp, recombinant VacA protein and pDsRED2-N1-HA/VacA plasmid were used for mechanistic investigation of VacA. In addition, we established mice infection models and evaluated gastric pathological changes. Results RNA sequencing and cellular experiments suggested that positive correlations between TRAF1 expression and NF-κB pathway activation and apoptosis. VacA increased the protein levels of TRAF1, 4-1BB, p-IKKα/β, phosphorylated p65, Bax, and the downstream inflammatory factor IL-8 but reduced that of Bcl-xl, promoting apoptosis and inhibiting proliferation in vitro. Transient and stable overexpression of TRAF1 promoted VacA-induced 4-1BB expression, NF-κB pathways activation, apoptosis-related molecules levels, and downstream inflammatory factors secretion in gastric epithelial cells, whereas silencing of TRAF1 led to the opposite effects. Functionally, TRAF1 increased VacA-induced p65 nuclear translocation and transcriptional activity, leading to apoptosis. BAY11-7082 (an NF-κB inhibitor) or 4-1BB blocking antibody attenuated the promotive effect of TRAF1 overexpression on VacA-induced NF-κB pathway activation, apoptosis-related protein expression, and downstream inflammatory factors secretion in gastric epithelial cells, whereas 4-1BB agonist antibody reversed the inhibitory effect of TRAF1 silencing on VacA function. In vivo, the immunofluorescence of TRAF1, 4-1BB and NF-κB p65 at vacA + Hp colonization sites was increased, and TRAF1 expression increased gradually with prolonged infection, correlating with exacerbated gastric mucosal inflammation and damage. Hp eradication or BAY11-7082 treatment reversed TRAF1 expression in mouse mucosal tissue. Conclusions We revealed a novel VacA–TRAF1–NF-κB pathway–IL-8 signalling axis, exposing novel connections among Hp infection, inflammation and gastric tumorigenesis. Graphical Abstract

Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.

The present study was conducted in order to study the detailed molecular mechanism of tumor necrosis factor (TNF)-α in chronic obstructive pulmonary disease (COPD). The rats were treated with cigarette smoke (CS) and lipopolysaccharide (LPS) to establish the COPD model. Next, the changes in lung injury in COPD rats with TNF-α knockdown was tested. Meanwhile, the regulation of TNF-α on MAPK pathway and its downstream molecules (SOCS3/TRAF1) was determined by western blotting. On this basis, the activation of MAPK and inhibition of SOCS3/TRAF1 was also examined. Subsequently, the lung function was tested with the plethysmograph, the cells of bronchoalveolar lavage fluid was counted and classified. Furthermore, lung tissue sections were stained with hematoxylin and eosin to verify whether the treatment of MAPK pathway and downstream molecules affected the effect of TNF-α knockdown on COPD. The present study showed that TNF-α knockdown could alleviate the decrease in the function and inflammatory injury of the lungs of rats with COPD. Western blot analysis verified that TNF-α knockdown could inhibit the activation of MAPK pathway and increase the expression of SOCS3/TRAF1. The following experimental results showed that the relief of lung injury caused by TNF-α knockdown could be deteriorated by activating MAPK pathway. It was also found that the symptom of COPD was decreased following transfection with sh-TNF-α but worsened by SOCS3/TRAF1 knockdown. Overall, TNF-α knockdown inhibited the activation of MAPK pathway and increased the expression of SOCS3/TRAF1, thus delaying the process of COPD.

Background: Hepatic macrophages play an indispensable role in liver pathophysiology, serving as key orchestrators of both liver injury and repair processes. ATG16L1 (autophagy‐related 16 like 1) has emerged as a novel and critical autophagy marker. In macrophages, ATG16L1 assumes a particularly crucial role. The current understanding of how macrophage ATG16L1 regulates liver inflammation in the context of liver fibrosis is unclear. Methods: This study included clinical patient samples of liver fibrosis and established a murine model with myeloid‐specific Atg16l1 knockout, creating a mouse model of liver fibrosis. Employing RNA sequencing, we sought to elucidate the mechanisms of macrophage ATG16L1 in liver fibrosis by identifying critical signaling pathways. To assess the influence of macrophage ATG16L1 on hepatocyte apoptosis and hepatic stellate cell (HSC) activation, we constructed a dedicated culture system. Ultimately, the introduction of mice with myeloid‐specific Atg16l1 knock‐in substantiated the protective role of myeloid‐specific Atg16l1 against inflammatory signaling, hepatocyte apoptosis, and activation of HSCs. Results: An upregulation of the ATG16L1 signal was observed in the liver tissues of patients with liver fibrosis and in fibrotic mice, predominantly localized to hepatic macrophages. In Atg16l1 Δ Mφ mice afflicted with liver fibrosis, we detected exacerbated liver damage, evidenced by heightened inflammatory signal expression, increased hepatocyte apoptosis, and enhanced activation of HSCs. The absence of macrophage Atg16l1 was found to result in elevated TNF receptor‐associated factor 1 (TRAF1) signaling, triggering inflammatory activation, intensifying hepatocyte apoptosis, and facilitating HSC activation through the transforming growth factor beta 1 (TGF‐ β 1) signaling. The detrimental effects of macrophage Atg16l1 depletion were demonstrated to be mitigated upon Atg16l1 reintroduction. Conclusions: This research delved into the mechanisms by which the macrophage ATG16L1 signal influences inflammatory signaling, hepatocyte apoptosis, and activation of HSCs in liver fibrosis. Consequently, it offers theoretical substantiation and an experimental groundwork for the identification of biological targets for therapeutic intervention in liver fibrosis.

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.

Background Infantile pneumonia (IP) is a leading cause of morbidity and mortality in children worldwide, with limited treatment options. Tumor necrosis factor receptor-associated factor 1 (TRAF1) has been implicated in the pathogenesis of various inflammatory diseases. Given the lack of effective therapies in IP, understanding the role of TRAF1 in regulating IP is crucial for developing new therapeutic strategies. Methods This study utilized in vitro and in vivo models to investigate the role of TRAF1 in IP. WI-38 cells were stimulated with lipopolysaccharide (LPS), and rats were administered LPS to mimic IP. The mRNA expression of TRAF1 and Sp1 transcription factor (SP1) was analyzed using quantitative real-time polymerase chain reaction. The protein expression of TRAF1, ubiquitin-specific peptidase 7 (USP7), and SP1 was detected by western blotting. Cell viability and apoptosis were assessed using cell counting kit-8 assay and flow cytometry/TUNEL assays, respectively. Interleukin-6 and tumor necrosis factor-α levels were measured by enzyme-linked immunosorbent assays. Reactive oxygen species and malondialdehyde levels were analyzed using fluorescence microscopy and colorimetric assays. The interactions among USP7, TRAF1, and SP1 were identified using co-immunoprecipitation assay, immunofluorescence assay, and dual-luciferase reporter assay. TRAF1 silencing-induced effects were validated in a rat model. Lung tissue pathology was assessed using haematoxylin and eosin assay and Massion assay. Results LPS treatment induced apoptosis, inflammation, and oxidative stress of WI-38 cells, however, TRAF1 silencing ameliorated these effects. USP7 stabilized TRAF1 protein expression through its deubiquitinating activity, while TRAF1 overexpression reversed the effects of USP7 silencing in LPS-treated WI-38 cells. In addition, SP1 transcriptionally activated TRAF1 in WI-38 cells. Further, TRAF1 silencing improved lung injury in LPS-induced mice. Conclusion Activation of TRAF1 by USP7/SP1 exacerbated the severity of IP, suggesting that targeting TRAF1 may have significant clinical implications for the treatment of IP.

The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as well as inflammasome-dependent IL-1β secretion. Importantly, TRAF1 polymorphisms have been strongly linked to an increased risk of rheumatoid arthritis (RA). However, whether and how TRAF1 contributes to RA pathogenesis is not fully understood. Moreover, investigating the role of TRAF1 in driving RA pathogenesis is complicated by its multifaceted and opposing roles in various immune cells. In this study, we subjected wildtype (WT) mice to the collagen antibody-induced arthritis (CAIA) model of RA and injected them intra-articularly with WT- or TRAF1-deficient macrophages. We show that mice injected with TRAF1-deficient macrophages exhibited significantly exacerbated joint inflammation, immune cell infiltration, and tissue damage compared to mice injected with WT macrophages. This study may lay the groundwork for novel therapies for RA that target TRAF1 in macrophages.