PROSITE documentation PDOC00224

TNF family signature and profile

The following cytokines can be grouped into a family on the basis of sequence, functional, and structural similarities [1,2,3]:

• Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-α) [4,5] is a cytokine which has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; finally, it can stimulate cell proliferation and induce cell differentiation under certain conditions.
• Lymphotoxin-α (LT-α) and lymphotoxin-β (LT-β), two related cytokines produced by lymphocytes and which are cytotoxic for a wide range of tumor cells in vitro and in vivo [6].
• T cell antigen gp39 (CD40L), a cytokine which seems to be important in B- cell development and activation.
• CD27L, a cytokine which plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.
• CD30L, a cytokine which induces proliferation of T cells.
• FASL, a cytokine involved in cell death [7].
• 4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation.
• OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production [8].
• TNF-related apoptosis inducing ligand (TRAIL) [9], a cytokine that induces apoptosis [9].

TNF-α is synthesized as a type II membrane protein which then undergoes post-translational cleavage liberating the extracellular domain. CD27L, CD30L, CD40L, FASL, LT-β, 4-1BBL and TRAIL also appear to be type II membrane proteins. LT-α is a secreted protein. All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-α/β) complexes that are recognized by their specific receptors.

As a signature for this family of proteins, we have selected the most conserved region. This region is located in a β-strand in the central section of these proteins.