The role of TRADD in death receptor signaling

TRADD (TNFR1-associated death domain protein) was initially identified as an adaptor molecule that transduces the signal downstream of the TNFR1 (tumor necrosis factor receptor 1). TNFR1 belongs to the so-called death receptor (DR) family of receptors that depending on the context can induce either apoptosis or proliferation, as well as NF-κB and MAP kinase activation. The receptors of this group contain death domain (DD) that is necessary for the induction of apoptosis. This review summarizes the recent advances in the field of DR signaling and in particular the role of TRADD.     

The role of TRADD in death receptor signaling

TRADD (TNFR1-associated death domain protein) was initially identified as an adaptor molecule that transduces the signal downstream of the TNFR1 (tumor necrosis factor receptor 1). TNFR1 belongs to the so-called death receptor (DR) family of receptors that depending on the context can induce either apoptosis or proliferation, as well as NF-κB and MAP kinase activation. The receptors of this group contain death domain (DD) that is necessary for the induction of apoptosis. This review summarizes the recent advances in the field of DR signaling and in particular the role of TRADD.     

The role of lymphotoxin signaling in the development of autoimmune pancreatitis and associated secondary extra-pancreatic pathologies

The pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis, have so far remained elusive. Treatment options for AIP are currently limited and disease relapse is frequent. Still, AIP can be characterized by specific clinical and histologic features. It has turned out that as described in other autoimmune diseases the generation of tertiary lymphoid organs is also a hallmark of patients with AIP. We have recently demonstrated that pancreata derived from human AIP patients display overexpression of lymphotoxin (LT) α and β and LTβR-target genes expressed by immune cells but also by irradiation resistant cells of the pancreas (e.g. acinar cells). Expression of LT α and β on acinar cells in murine pancreata Tg(Ela1-Lta,b) mice led to chronic pancreatitis and sufficed to reproduce key features of human AIP including the development of autoimmunity and AIP associated secondary extra pancreatic pathologies. Here, we review how aberrant and ectopic expression of LT α and β can induce inflammation and autoimmune diseases in general and how this knowledge might specifically lead to an alternative treatment for patients suffering from autoimmune pancreatitis.     

The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells

Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-beta receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTalpha, LTbeta, LTbetaR, and the NFkappaB inducing kinase show a specific loss of CD8- DC subsets. In contrast, the CD8alpha- DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM- and BTLA-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LTbetaR was necessary to maintain homeostasis. Moreover, enforced activation of the LTbetaR with an agonist Ab drove expansion of CD8alpha- DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LTbetaR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.     

The MYND domain-containing protein BRAM1 inhibits lymphotoxin beta receptor-mediated signaling through affecting receptor oligomerization

MYND (myeloid-Nervy-DEAF-1) domains exist in a large number of proteins that are functionally important in development or associated with cancers. We have previously demonstrated that a MYND domain-containing protein, the bone morphogenesis protein receptor-associated molecule 1 (BRAM1), is able to interact with Epstein-Barr virus-encoded latent membrane protein 1 (LMP1), which acts as a constitutively activated tumor necrosis factor receptor (TNFR). Herein we further demonstrated that BRAM1 additionally associates with the TNFR-superfamily member, the lymphotoxin beta receptor (LTβR), and hence inhibits LTβR-mediated function. Using the yeast two-hybrid assay, we demonstrated that BRAM1 interacts with LTβR mainly through the self-association domain of LTβR (aa 336-398). The co-immunoprecipitation experiment further revealed that BRAM1 as well as MYND domain-containing proteins, MTG8 and DEAF-1, interacts with LTβR via their MYND domains. The BRAM1-LTβR interaction impedes the self-association of LTβR and the recruitment of TNFR-associated factors 2 and 3 (TRAF2 and TRAF3), leading to abolishment of LTβR-induced NF-κB signaling, JNK activation, and caspase-dependent cell death. In sum, our data demonstrate that the MYND-containing protein BRAM1 abrogates LTβR function through a protein-protein interaction. These findings may provide a direction for the treatment of dysregulation of LTβR-mediated signaling.     

The role of receptor internalization in CD95 signaling

Activation of the cell surface CD95 receptor triggers a cascade of signaling events, including assembly of the death-inducing signaling complex (DISC), that culminate in cellular apoptosis. In this study, we demonstrate a general requirement of receptor internalization for CD95 ligand-mediated DISC amplification, caspase activation and apoptosis in type I cells. Recruitment of DISC components to the activated receptor predominantly occurs after the receptor has moved into an endosomal compartment and blockade of CD95 internalization impairs DISC formation and apoptosis. In contrast, CD95 ligand stimulation of cells unable to internalize CD95 results in activation of proliferative Erk and NF-kappaB signaling pathways. Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates.     

Antigen receptor signaling in the rheumatic diseases

Antigen receptor signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythema-tosus in mice and humans. Impaired and enhanced T-cell receptor signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.     

The signaling pathway of uromodulin and its role in kidney diseases

Abstract

The uromodulin (UMOD) is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. UMOD acts as a regulatory protein in health and in various conditions. For kidney diseases, its role remains elusive. On one hand, UMOD plays a role in binding and excretion of various potentially injurious products from the tubular fluid. On the other hand, chronic kidney disease is associated with higher serum levels of UMOD. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for UMOD to the investigators who were interested in the role of UMOD in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of UMOD and its role in the pathogenesis of kidney diseases.     

The central role of Fas-ligand cell signaling in inflammatory lung diseases

Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1 beta and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.     

Intestinal cryptopatch formation in mice requires lymphotoxin alpha and the lymphotoxin beta receptor

Interactions between lymphotoxin (LT)alpha(1)beta(2) on inducer cells and the lymphotoxin beta receptor (LTbetaR) on stromal cells initiate development of lymph nodes and Peyer's patches. In this study, we assessed the contributions of LTalpha and LTbetaR to the development of cryptopatches (CP), aggregates of T cell precursors in the mouse small intestine. Mice genetically deficient in LTalpha or LTbetaR lacked CP. Bone marrow from LTalpha-deficient mice was unable to initiate development of CP or isolated lymphoid follicles (ILF) after transfer to CD132-null mice lacking CP and ILF. However, LTalpha-deficient bone marrow-derived cells contributed to CP formed in CD132-null mice receiving a mixture of wild-type and LTalpha-deficient bone marrow cells. Transfer of wild-type bone marrow into irradiated LTalpha-deficient mice resulted in reconstitution of both CP and ILF. However, the LT-dependent formation of CP was distinguished from the LT-dependent formation of ILF and Peyer's patches by not requiring the presence of an intact NF-kappaB-inducing kinase gene. CP but not ILF were present in the small intestine from NF-kappaB-inducing kinase-deficient alymphoplasia mice, indicating that the alternate NF-kappaB activation pathway required for other types of LTbetaR-dependent lymphoid organogenesis is dispensable for CP development. In addition, we identified VCAM-1(+) cells within both CP and ILF that are candidates for the stromal cells involved in receiving LT-dependent signals from the hemopoietic precursors recruited to CP. These findings demonstrate that interactions between cells expressing LTalpha(1)beta(2) and LTbetaR are a shared feature in the development of all small intestinal lymphoid aggregates.     

The signaling pathway of NADPH oxidase and its role in glomerular diseases

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), a major source of reactive oxygen species, is a critical mediator of redox signaling. It is well-documented that oxidative stress is associated with the development of glomerular diseases (GN). Hence, the Nox was also thought to be involved in the pathogenesis of GN. However, the expression of Nox in various GN was not consistent, the mechanisms by which the activity of the Nox enzymes in regulating renal cells remains unclear. Signaling pathways might be very important in the pathogenesis of GN. We performed this review to provide a relatively complete signaling pathways flowchart for Nox to the investigators who were interested in the role of Nox in the pathogenesis of GN. Here, we reviewed the signal transduction pathway of Nox and its role in the pathogenesis of GN.     

The signaling pathway of hypoxia inducible factor and its role in renal diseases

Abstract

It is well-documented that hypoxia inducible factor (HIF) is a key mediator of tissue and cellular adaptation to hypoxia. HIF-target genes are also involved in cellular apoptosis and profibrotic mechanisms. The role of HIF in diseases is not consistent. It is a risk factor for tumor progression, whereas it plays a protective role against ischemic hypofusion. For renal diseases, it is not always a risk or protective factor. Many factors are involved in the pathogenesis of renal diseases. It is reported that HIF not only increases hypoxia tolerance, but also regulates a lot of signaling pathways. In the past decades, a number of studies were also conducted to explore the association between HIF and the risk of renal diseases. However, the role of HIF in the development of renal diseases was not entirely clear. In this study, the signal transduction pathways of HIF and its role in the pathogenesis of renal diseases were reviewed.     

The role of subunit cooperativity on ryanodine receptor 2 calcium signaling

The ryanodine receptor type 2 (RyR2) is composed of four subunits that control calcium (Ca) release in cardiac cells. RyR2 serves primarily as a Ca sensor and can respond to rapid sub-millisecond pulses of Ca while remaining shut at resting concentrations. However, it is not known how the four subunits interact for the RyR2 to function as an effective Ca sensor. To address this question, and to understand the role of subunit cooperativity in Ca-mediated signal transduction, we have developed a computational model of the RyR2 composed of four interacting subunits. We first analyze the statistical properties of a single RyR2 tetramer, where each subunit can exist in a closed or open conformation. Our findings indicate that the number of subunits in the open state is a crucial parameter that dictates RyR2 kinetics. We find that three or four open subunits are required for the RyR2 to harness cooperative interactions to respond to sub-millisecond changes in Ca, while at the same time remaining shut at the resting Ca levels in the cardiac cell. If the required number of open subunits is lowered to one or two, the RyR2 cannot serve as a robust Ca sensor, as the large cooperativity required to stabilize the closed state prevents channel activation. Using this four-subunit model, we analyze the kinetics of Ca release from a RyR2 cluster. We show that the closure of a cluster of RyR2 channels is highly sensitive to the balance of cooperative interactions between closed and open subunits. Based on this result, we analyze how specific interactions between RyR2 subunits can induce persistent Ca leak from the sarcoplasmic reticulum (SR), which is believed to be arrhythmogenic. Thus, these results provide a framework to analyze how a pharmacologic or genetic modification of RyR2 subunit cooperativity can induce abnormal Ca cycling that can potentially lead to life-threatening arrhythmias.     

The role of lymphotoxin in development and maintenance of secondary lymphoid tissues

Secondary lymphoid organs provide the necessary microenvironment for the cooperation of antigen-specific T- and B-lymphocytes and antigen-presenting cells in order to initiate an efficient immune response. Remarkable progress in understanding of the mechanisms of lymphoid organogenesis was achieved due to the analysis of various gene-targeted mice. This review primarily focuses on the role of lymphotoxin (LT) in development, maturation and maintenance of secondary lymphoid organs.     

A role for lymphotoxin in primary Sjogren's disease

The etiology of salivary gland injury in primary Sj?gren's disease is not well understood. We have previously described a mouse model of Sj?gren's disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sj?gren's disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA(-/-) mice, the IL14αTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA(-/-) mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sj?gren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sj?gren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sj?gren's disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.     

The role of disulfide-linked dimerization in interleukin-3 receptor signaling and biological activity

Cysteine residues 86 and 91 of the beta subunit of the human interleukin (hIL)-3 receptor (hbetac) participate in disulfide-linked receptor subunit heterodimerization. This linkage is essential for receptor tyrosine phosphorylation, since the Cys-86 --> Ala (Mc4) and Cys-91 --> Ala (Mc5) mutations abolished both events. Here, we used these mutants to examine whether disulfide-linked receptor dimerization affects the biological and biochemical activities of the IL-3 receptor. Murine T cells expressing hIL-3Ralpha and Mc4 or Mc5 did not proliferate in hIL-3, whereas cells expressing wild-type hbetac exhibited rapid proliferation. However, a small subpopulation of cells expressing each mutant could be selected for growth in IL-3, and these proliferated similarly to cells expressing wild-type hbetac, despite failing to undergo IL-3-stimulated hbetac tyrosine phosphorylation. The Mc4 and Mc5 mutations substantially reduced, but did not abrogate, IL-3-mediated anti-apoptotic activity in the unselected populations. Moreover, the mutations abolished IL-3-induced JAK2, STAT, and AKT activation in the unselected cells, whereas activation of these molecules in IL-3-selected cells was normal. In contrast, Mc4 and Mc5 showed a limited effect on activation of Erk1 and -2 in unselected cells. These data suggest that whereas disulfide-mediated cross-linking and hbetac tyrosine phosphorylation are normally important for receptor activation, alternative mechanisms can bypass these requirements.     

The signaling pathway of stromal cell-derived factor-1 and its role in kidney diseases

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) regulates the trafficking of progenitor cell (PGC) during embryonic development, cell chemotaxis, and postnatal homing into injury sites. SDF-1 also regulates cell growth, survival, adhesion and angiogenesis. However, in different tissues/cells, the role of SDF-1 is different, such as that it is increased in most of the tumors and associated with cancer metastasis, whereas it is essential for the development of vasculature. For kidney diseases, its role remains controversial. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for SDF-1 to the investigators who were interested in the role of SDF-1 in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of SDF-1 and its role in the pathogenesis of kidney diseases.