The TNF and TNF Receptor Superfamilies Integrating Mammalian Biology

The receptors and ligands in this superfamily have unique structural attributes that couple them directly to signaling pathways for cell proliferation, survival, and differentiation. Thus, they have assumed prominent roles in the generation of tissues and transient microen-capabilities are crucial in coordinating the proliferation and protective functions of pathogen-reactive cells. Here, we review the organization of the TNF/TNFR SF and how these proteins have been adapted for pro-Bethesda, Maryland 20892 cesses as seemingly disparate as host defense and or-ganogenesis. In interpreting this large and highly active area of research, we have focused on common themes Introduction that unite the actions of these genes in different tissues. We also discuss the evolutionary success of this super-Three decades ago, lymphotoxin (LT) and tumor necro-sis factor (TNF) were identified as products of lympho-family—success that we infer from its expansion across the mammalian genome and from its many indispens-cytes and macrophages that caused the lysis of certain types of cells, especially tumor cells (Granger et al., able roles in mammalian biology.The normal functions of TNF/TNFR SFPs, as well as ally, it became clear that they were members of a gene certain diseases involving them, depend on the obliga-superfamily. Not surprisingly, the receptors for these tory 3-fold symmetry that defines the essential signaling proteins also constitute a TNF receptor (TNFR)-related stoichiometry and structure (Figure 1). The ligands are gene superfamily. Large-scale sequencing of " ex-type 2 proteins that can have both membrane-embed-pressed sequence tags " (ESTs) identified many related ded " pro " as well as cleaved, soluble " mature " forms proteins, collectively referred to here as TNF-and TNFR-(for review, see Idriss and Naismith, 2000). Both forms related superfamily proteins (TNF/TNFR SFPs; reviewed are active as self-assembling noncovalent trimers, whose individual chains fold as compact " jellyroll " ␤ sandwiches and interact at hydrophobic interfaces (Fesik, UCL.ac.uk/users/hester/tnfinfo.html). The familiar as 2000) (Figure 1A). The 25%–30% amino acid similarity well as standardized names of these proteins are listed between TNF-like ligands is largely confined to internal in Table 1, together with their gene locations, pheno-aromatic residues responsible for trimer assembly. The types caused by mutations in these genes, and identified external surfaces of ligand trimers show little sequence functions. similarity, which accounts for receptor selectivity (Figure The discovery that cachectin, a protein known to 2). The ligand shape is that of an inverted bell that is cause fever and wasting, was identical to TNF provided …