**5. Death receptors**

Death receptors belong to the TNF-R superfamily of receptors. They participate in proliferation, differentiation, immune response, gene expression, survival and cell death. In fact, TNF-R1 and Fas (CD95/APO-1) are involved in apoptotic processes [30]. Death receptors are stimulated by death ligands: TNF; Fas ligand (FasL) and **T**NF-**r**elated **a**poptosis-**i**nducing **l**igand (TRAIL). Death receptors contain an intracellular globular interaction domain called death domain (DD). Upon ligand binding, death receptors aggregate forming trimers. As a consequence of this aggregation, they recruit adaptors such as FADD, which interacts with caspase-8 by virtue of its death effector domain (DED), forming the multi-protein complex known as DISC. However, in some instances, death receptors can oligomerize in the abscence of ligand binding. For example, they can be activated by UV radiation [31]. Fas and TNF-R1 can also recruit **R**IP (receptor-interacting protein) -**a**ssociated **I**ch-1/CED homologous [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with **d**eath **d**omain (RAIDD) which activates caspase-2 through a **c**aspase **a**ctivation and **r**ecruitment **d**omain (CARD). In addition, death receptors can participate in caspase-independent mechanisms. For instance, TNF-R1 can activate Extracellular signal-regulated kinase 2 (Erk2) through the **m**itogenactivated kinase **a**ctivating **d**eath **d**omain (MADD) protein [32]. Fas can bind Death-domain associated protein (Daxx) and activate c-Jun amino-terminal kinase (JNK) [33]. **T**NF-**r**eceptor **a**ssociated **d**eath **d**omain (TRADD) and RIP can activate Nuclear factor kappa-light-chainenhancer of activated B cells (NFkB), triggering a form of regulated necrosis named **necroptosis** [34].
