TWEAK shall inherit the earth

Abstract

Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis. 3 TWEAK is a type II transmembrane protein (extracellular C-terminus) that can undergo proteolysis to produce an active soluble homotrimer, 4,5 whereas FN14 is a type Ia transmembrane protein. 6 In some respects the potent effects of the ligand TWEAK are reminiscent to those of TNFa: both factors appear to play roles in inflammation, and both have the capacity to induce cell death, although usually in conjunction with another stimulus. Responses to TNFSF ligands can be complex because several ligands often bind to the same receptor and vice versa. For example, both the human ligands TNFa and LTa bind the receptors TNFR1 and TNFR2, whereas LTa also binds HVEM. In fact, more than half of the TNSF ligands bind to at least two receptors. 7 One of the amazing things about the TWEAK/FN14 system is that it is a simple, single ligand, single receptor system 7 in which the intracellular signalling domain of FN14 is only 28 amino acids. It remains possible that another TWEAK receptor exists 8 which might help to explain the diverse range of effects that TWEAK produces, but this is yet to be conclusively established.

Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

“…The range of activities of the TWEAK/Fn14 system and the tissue damage/injury-associated expression pattern of Fn14 argue for a role of TWEAK and Fn14 in wound healing, tissue repair, regeneration, and maintenance of tissue homeostasis. 11 In line with this, it has been found that TWEAK and Fn14 are required for the regenerative responses occurring after muscle injury, partial hepatectomy, and partial pancreatectomy. [12][13][14] In the case of exaggerated or chronic activation, however, the TWEAK/Fn14 system may also contribute to tissue injury.…”

TWEAK Induces Apoptosis through a Death-signaling Complex Comprising Receptor-interacting Protein 1 (RIP1), Fas-associated Death Domain (FADD), and Caspase-8

“…TWEAK is capable of inducing a number of diverse cell functions, including proliferation, differentiation, migration, and cell death, depending on cellular context (3,5,7). The ability of TWEAK to induce apoptosis in certain cells has been perplexing, given that its cognate receptor, FN14, lacks a cytoplasmic death domain.…”

“…Subsequent studies revealed that TWEAK activates a number of additional cellular functions including proliferation, differentiation, and migration (3)(4)(5)(6)(7). TWEAK is expressed in a variety of tissues and by certain types of immune cells and cancer cell lines.…”

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

“…Strategies that could be useful for therapeutic targeting of this axis will also be discussed. The reader is referred to recent review articles by Vince and Silke 16 and Burkly et al 17 for additional information on the TWEAK-Fn14 axis and other perspectives on its likely function in normal and diseased tissues.…”