The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response. Here we show that tumour necrosis factor receptor-associated factor 3 (TRAF3) is upregulated in mouse and human livers with hepatic steatosis. After 24 weeks on a high-fat diet (HFD), obesity, insulin resistance, hepatic steatosis and inflammatory responses are significantly ameliorated in liver-specific TRAF3-knockout mice, but exacerbated in transgenic mice overexpressing TRAF3 in hepatocytes. The detrimental effects of TRAF3 on hepatic steatosis and related pathologies are confirmed in ob/ob mice. We further show that in response to HFD, hepatocyte TRAF3 binds to TGF-β-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent autophosphorylation, thereby enhancing the activation of downstream IKKβ–NF-κB and MKK–JNK–IRS1307 signalling cascades, while disrupting AKT–GSK3β/FOXO1 signalling. The TRAF3–TAK1 interaction and TAK1 ubiquitination are indispensable for TRAF3-regulated hepatic steatosis. In conclusion, hepatocyte TRAF3 promotes HFD-induced or genetic hepatic steatosis in a TAK1-dependent manner.

No abstract

No abstract

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor–associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase–, nuclear factor κB– and Rac-1–induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β–activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3–TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3–TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.

356D espite recent treatment advances, chronic heart failure still carries a poor prognosis and continues to be a major health challenge in worldwide.1,2 Cardiac hypertrophy, occurring in response to pathological stimuli, such as hypertension or ischemia, is a major risk factor for the development of heart failure.3 Numerous intracellular signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade and the mitogen-activated protein kinase (MAPK) pathway initiate and propagate hypertrophic myocardial growth. 4,5 After PI3K activation by cardiac hypertrophic stress, phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and thereby activates AKT, which subsequently induces hypertrophy via regulating downstream molecules, including inactivation of glycogen synthase kinase-3β (GSK3β) and activation of mammalian target of rapamycin (mTOR) and p70S6 kinase. [5][6][7] However, the underlying mechanisms of cardiac hypertrophy and the resultant heart failure remain unclear.Tumor necrosis factor receptor-associated factors (TRAFs) are a family of cytoplasmic adaptor proteins with critical functions in the signaling pathways initiated by tumor necrosis factor receptors, toll-like receptors, and interleukin-1 receptors.8 Consistent with the functions of other TRAF family members, TRAF3 regulates the activities of several signaling pathways. However, TRAF3 has a unique manner of coordinating signaling events. Previous studies have demonstrated that TRAF3 degradation after CD40 engagement in B cells leads to the release of MAPK kinase kinase 1, transforming growth factor β-activated kinase 1, and nuclear factor-κB (NF-κB)-inducing kinase into the cytoplasm, ultimately leading to MAPK and IκB kinase-α (IKK-α) activation. 9,10 Other studies have reported that TRAF3 binds to PI3K 11,12 ; this binding is correlated with the level of TRAF3 ubiquitination, which is crucial for the effect of TRAF3 on CD40-associated AKT activation.11 Although the MAPK, NF-κB, and AKT signaling pathways all contribute to the development of cardiac Abstract-Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways.Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II-or phenylephrineinduced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli...

No abstract