TRAFs

TRAFs, or TNF receptor-associated factors, are a family of adaptor proteins and, in some cases, E3 ubiquitin ligases that relay signals from members of the TNF receptor superfamily and related receptors to intracellular pathways. They participate in signaling that regulates inflammation, immunity, cell survival, and apoptosis.

Most TRAFs share a conserved C-terminal TRAF domain that mediates trimerization and receptor or adaptor binding, and an N-terminal region that varies among family members. Several TRAFs contain a RING finger or zinc-binding motif that confers E3 ubiquitin ligase activity; others act primarily as scaffolds for assembling signaling complexes.

In signaling, TRAFs recruit kinases such as TAK1 and components of the IKK and MAPK cascades, promoting activation of NF-κB and AP-1 transcription factors. They operate downstream of multiple receptors, including TNFR1, CD40, BAFF-R and RANK, as well as Toll-like receptors and IL-1 receptor family members, integrating inputs from innate and adaptive immunity.

Biological roles include regulation of B cell development, osteoclast differentiation, and inflammatory responses. Among the family, TRAF6 is particularly important for RANK signaling and bone metabolism.

Dysregulation of TRAF signaling has been linked to immunodeficiency, autoimmunity, inflammatory diseases and cancer; because of their central role, TRAFs are targets of ongoing research for therapeutic modulation.