![traf protein scaffold traf protein scaffold](https://d3i71xaburhd42.cloudfront.net/53679fd8e0f6f923341cfc34ade94ae432619651/6-Figure3-1.png)
TNF Receptor Associated Factors (TRAFs) are a family of 6 proteins (TRAF1 to 6) characterized for having a protein region composed by a coiled coil followed by a seven-eight anti-parallel β-sheets at the C-terminus of the protein forming what has been coined as the TRAF domain (TD) ( 1, 2). Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.īrief Introduction to the TRAF Protein Family Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. 7Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, SpainĬD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain.6Instituto de Investigacion Sanitaria de Navarra, Pamplona, Spain.5Departamento de Inmunologia e Inmunoterapia, Clinica Universitaria, Universidad de Navarra, Pamplona, Spain.3Departamento de Inmunologia and Inmunoterapia, Centro de Investigación Medica Aplicada, Universidad de Navarra, Pamplona, Spain.2Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.1Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain.Zapata 1,2 *, Gema Perez-Chacon 1,2, Pablo Carr-Baena 1, Ivan Martinez-Forero 3, Arantza Azpilikueta 3, Itziar Otano 3 and Ignacio Melero 3,4,5,6,7 *