The design and characterization of receptor-selective APRIL variants.

A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily with an important role in humoral immunity, is also implicated in several cancers as a prosurvival factor. APRIL binds two different TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligand interactor (TACI), and also interacts independently with heparan sulfate proteoglycans. Because APRIL shares binding of the TNF receptors with B cell activation factor, separating the precise signaling pathways activated by either ligand in a given context has proven quite difficult.

Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease.

The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise multidomain proteins with diverse roles in cell activation, proliferation and cell death. These proteins play pivotal roles in the initiation, maintenance and termination of immune responses and have vital roles outside the immune system. The discovery and analysis of diseases associated with mutations in these families has revealed crucial mechanistic details of their normal functions.

Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas.

APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross-linking of APRIL and efficient signaling.

Disruption of heparan sulfate proteoglycan conformation perturbs B-cell maturation and APRIL-mediated plasma cell survival.

The development and antigen-dependent differentiation of B lymphocytes are orchestrated by an array of growth factors, cytokines, and chemokines that require tight spatiotemporal regulation. Heparan sulfate proteoglycans specifically bind and regulate the bioavailability of soluble protein ligands, but their role in the immune system has remained largely unexplored. Modification of heparan sulfate by glucuronyl C5-epimerase (Glce) controls heparan sulfate-chain flexibility and thereby affects ligand binding.

APRIL in B-cell malignancies and autoimmunity.

A Proliferation Inducing Ligand (APRIL) was first identified as a cytokine expressed predominantly by tumour tissues and was not found in most normal tissues. The activity of this new cytokine, in terms of its ability to stimulate tumour cell proliferation in vivo, determined the catchy acronym of yet another TNF family cytokine: APRIL. Reports showing an association between APRIL and cancer have since been prolific, in particular, those showing a link with B cell malignancies.

The proteoglycan (heparan sulfate proteoglycan) binding domain of APRIL serves as a platform for ligand multimerization and cross-linking.

A proliferation-inducing ligand (APRIL) (also known as TALL-2 and TRDL-1) is a member of the tumor necrosis factor (TNF) superfamily that has tumorigenic properties but is also important for the induction of humoral immune responses. APRIL binds two TNF receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) as well as heparan sulfate proteoglycans (HSPGs). The aim of this study was to clarify the role of the HSPG interaction in canonical APRIL signaling, because it has been proposed to act as a docking site and also to play a role in direct signaling.

"APRIL hath put a spring of youth in everything": Relevance of APRIL for survival.

A proliferation inducing ligand (APRIL or TALL-2 and TRDL-1) was first discovered as a cytokine over-expressed in many transformed cells and with the capacity to stimulate proliferation. APRIL was shown to bind two different receptors of the TNF receptor superfamily: B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), as well as heparan sulphate proteoglycans (HSPGs). APRIL has since been shown to play a physiological role in B cell biology, in particular the survival of plasma B cells in a specialized APRIL-rich niche.

Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome.

TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1.

Alternative roles for CD59.

CD59 was first identified as a regulator of the terminal pathway of complement, which acts by binding to the C8/C9 components of the assembling membrane attack complex (MAC), to inhibit formation of the lytic pore. Structurally, CD59 is a small, highly glycosylated, GPI-linked protein, with a wide expression profile. Functionally, the role of CD59 in complement regulation is well-defined but studies have also shown clear evidence for signalling properties, which are linked to its glycophosphatidyl inositol (GPI) anchor and its location within lipid rafts.

Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS).

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse "knock-in" model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes.

Expression of TRAIL and TRAIL receptors in normal and malignant tissues.

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, is a member of the TNF family of proteins. Tumour cells were initially found to have increased sensitivity to TRAIL compared with normal cells, raising hopes that TRAIL would prove useful as an anti-tumor agent. The production of reliable monoclonal antibodies against TRAIL and its receptors that can stain fixed specimens will allow a thorough analysis of their expression on normal and malignant tissues.

Following a TRAIL: update on a ligand and its five receptors.

Identification of tumour necrosis factor apoptosis inducing ligand (TRAIL), a TNF family ligand, sparked a torrent of research, following an initial observation that it could kill tumour cells, but spare normal cells. Almost a decade after its discovery, and with five known receptors, the true physiological role of TRAIL is still debated and its anti-tumorigenic properties limited by potential toxicity. This review takes a comprehensive look at the story of this enigmatic ligand, addressing its remaining potential as a therapeutic and providing an overview of the TRAIL receptors themselves.