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Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of structurally related proteins that transduces signals from members of TNFR superfamily and various other immune receptors. Major downstream signaling events mediated by the TRAF molecules include activation of the transcription factor nuclear factor κB (NF-κB) and the mitogen-activated protein kinases (MAPKs). In addition, some TRAF family members, particularly TRAF2 and TRAF3, serve as negative regulators of specific signaling pathways, such as the noncanonical NF-κB and proinflammatory toll-like receptor pathways. Thus, TRAFs possess important and complex signaling functions in the immune system and play an important role in regulating immune and inflammatory responses. This review will focus on the role of TRAF proteins in the regulation of NF-κB and MAPK signaling pathways.

Senescent cells that have stopped proliferating secrete molecules that influence the cells around them. Prevention of this senescence-activated secretory phenotype seems to slow organismal aging. Kang et al. explored the regulatory process behind cell senescence and found that DNA damage led to stabilization of the transcription factor GATA4 (see the Perspective by Cassidy and Narita). Increased activity of GATA4 in senescent cells stimulated genes encoding secreted factors. GATA4 also accumulates in the brains of aging mice or humans. Science , this issue 10.1126/science.aaa5612 ; see also p. 1448 The transcription factor GATA4 promotes cell senescence. [Also see Perspective by Cassidy and Narita ] Cellular senescence is a terminal stress-activated program controlled by the p53 and p16 INK4a tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16 INK4a . GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

Eukaryotic cells use autophagy to recycle cellular components. During autophagy, autophagosomes deliver cytoplasmic contents to the vacuole or lysosome for breakdown. Mammalian cells regulate the dynamics of autophagy via ubiquitin-mediated proteolysis of autophagy proteins. Here, we show that the Tumor necrosis factor Receptor-Associated Factor (TRAF) family proteins TRAF1a and TRAF1b (previously named MUSE14 and MUSE13, respectively) help regulate autophagy via ubiquitination. Upon starvation, cytoplasmic TRAF1a and TRAF1b translocated to autophagosomes. Knockout lines showed reduced tolerance to nutrient deficiency, increased salicylic acid and reactive oxygen species levels, and constitutive cell death in rosettes, resembling the phenotypes of autophagy-defective mutants. Starvation-activated autophagosome accumulation decreased in root cells, indicating that TRAF1a and TRAF1b function redundantly in regulating autophagosome formation. TRAF1a and TRAF1b interacted in planta with ATG6 and the RING finger E3 ligases SINAT1, SINAT2, and SINAT6 (with a truncated RING-finger domain). SINAT1 and SINAT2 require the presence of TRAF1a and TRAF1b to ubiquitinate and destabilize AUTOPHAGY PROTEIN6 (ATG6) in vivo. Conversely, starvation-induced SINAT6 reduced SINAT1- and SINAT2-mediated ubiquitination and degradation of ATG6. Consistently, / and knockout mutants exhibited increased tolerance and sensitivity, respectively, to nutrient starvation. Therefore, TRAF1a and TRAF1b function as molecular adaptors that help regulate autophagy by modulating ATG6 stability in Arabidopsis.

The precise mechanisms of the thymic development T reg cells are still being determined. Farrar and colleagues demonstrate that signals from a triumvirate of members of the tumor-necrosis factor receptor superfamily are critical for T reg cell development in the thymus. Regulatory T cells (T reg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of T reg cells is undefined. We found here that T reg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of T reg cells. Conversely, TNFRSF agonists enhanced the differentiation of T reg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the T reg cell repertoire. In vivo , combined inhibition of GITR, OX40 and TNFR2 abrogated the development of T reg cells. Thus, expression of members of the TNFRSF on T reg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of T reg cells and shaped the T reg cell repertoire.

Studies showing how BAFF and its closely related homologue APRIL activate their receptors and transmit growth and survival signals to B cells have shed new light on the association between BAFF and autoimmunity. This knowledge has prompted several clinical trials testing BAFF and APRIL antagonists for the treatment of autoimmune diseases and lymphomas. Key Points Studies examining the binding of B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) to their receptors have revealed additional layers of complexity. Trimeric forms of both BAFF and APRIL bind to the receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), but only multimeric forms of these ligands can signal through this receptor. Recent work has provided a more detailed roadmap of BAFF-induced survival signalling. The activation of the alternative nuclear factor-κB2 (NF-κB2) pathway and of the phosphoinositide 3-kinase–AKT1–mammalian target of rapamycin pathway, and the upregulation of expression of myeloid cell leukaemia sequence 1 (MCL1) provide a rational basis for the effects of BAFF on B cell survival and metabolic fitness. The role of BAFF is no longer restricted to B cells. BAFF is also produced by non-haematopoietic cells and affects B cells as well as T cells, macrophages and dendritic cells. The role of BAFF in B cell tolerance is not what it seems. BAFF does not markedly affect the negative selection of high-affinity self-reactive B cells but instead increases the proliferation of positively selected low-affinity self-reactive B cells. BAFF mediates a unique form of autoimmune disease, which is independent of T cell involvement but requires the activation of innate immune mechanisms such as Toll-like receptor activation. BAFF and/or APRIL inhibitors have shown some benefits in the clinic, but there are many remaining challenges and possible future options in the form of combined therapies. The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.

Key Points Recent work examining the cell biology of Toll-like receptors (TLRs) illustrates how basic aspects of the cellular machinery contribute to receptor function and regulation. Despite residing on several organelles, all TLRs are first transported to the Golgi complex before being routed to the appropriate location. Bacterium-sensing TLRs probably follow the default secretory pathway from the Golgi to the cell surface, whereas TLRs that detect viral nucleic acids are delivered to endolysosomes by the chaperone Unc93B1. Compartment-specific activity of nucleic acid-sensing TLRs (for example, TLR7 and TLR9) is maintained by compartment-specific cleavage events that generate functional receptors. These cleavage events are probably mediated by lysosomal cathepsins, and consequently nucleic acid-sensing TLRs are only active in endolysosomes. Bacterium-sensing TLRs (such as TLR2 and TLR4) use sorting adaptor proteins to determine the subcellular sites of signal transduction. For TLR4, the sorting adaptors TIRAP (TIR domain-containing adaptor protein) and TRAM (TRIF-related adaptor molecule) function to recruit their downstream signalling machinery to the plasma membrane and endosomes, respectively. Sorting adaptor proteins are positioned in specific intracellular subcompartments by interacting with phosphoinositides. Regulators of phosphoinositide metabolism may therefore control the activity of specific TLR signalling pathways. Endolysosomes seem to be the sole subcompartments that allow a TLR-dependent interferon response. Consequently, the plasma membrane-localized TLR4 must first be internalized into endosomes before the interferon-inducing signalling pathway can be activated. The activation and signalling pathways engaged by Toll-like receptors (TLRs) are determined by their localization in the cell. Here, the authors explain how generic cellular machinery involved in the compartmentalization of receptors and signalling molecules contributes to TLR function and regulation. An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand–receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.

Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through the cag type 4 secretion system ( cag -T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detect H. pylori . Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detecting H. pylori ; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through the cag -T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-κB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-κB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis. IMPORTANCE H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance. H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance.

The auxiliary subunit Cavβ regulates calcium channel density in the plasma membrane, but the mechanism by which this occurs has been poorly defined. Altier et al . find that Cavβ prevents ubiquitination of the Cav1.2 channels by the RFP2 ubiquitin ligase and subsequent targeting of the channels for proteasomal degradation. It is well established that the auxiliary Cavβ subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cavβ subunit increased membrane expression of Cav1.2 channels by preventing the entry of the channels into the endoplasmic reticulum–associated protein degradation (ERAD) complex. Without Cavβ, Cav1.2 channels underwent robust ubiquitination by the RFP2 ubiquitin ligase and interacted with the ERAD complex proteins derlin-1 and p97, culminating in targeting of the channels to the proteasome for degradation. On treatment with the proteasomal inhibitor MG132, Cavβ-free channels were rescued from degradation and trafficked to the plasma membrane. The coexpression of Cavβ interfered with ubiquitination and targeting of the channel to the ERAD complex, thereby facilitating export from the endoplasmic reticulum and promoting expression on the cell surface. Thus, Cavββ regulates the ubiquitination and stability of the calcium channel complex.

Antiviral responses must rapidly defend against infection while minimizing inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that suppress protein levels by binding target sequences on their cognate mRNA. Here, we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses in primary mouse lung epithelial cells: influenza virus, EMCV, and VSV. We identified the transcriptional network regulated by miR-144 and demonstrate that miR-144 post-transcriptionally suppresses TRAF6 levels. In vivo ablation of miR-144 reduced influenza virus replication in the lung and disease severity. These data suggest that miR-144 reduces the antiviral response by attenuating the TRAF6-IRF7 pathway to alter the cellular antiviral transcriptional landscape.

TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll-IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review also offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation.