Programmed cell death can be initiated by intrinsic or extrinsic pathways. Extrinsic pathways involve the activation of death receptors (DRs), which triggers the formation of death-induced signaling complexes (DISCs) consisting of caspase-8 and fas-associated protein with death domain (FADD). DISC formation activates caspase-8, leading to apoptosis. Under certain conditions, caspase-8 and FADD have also been shown to suppress necroptosis. DR downstream signaling is regulated by various post-translational modifications, but FADD is only known to undergo phosphorylation, and this modification is not involved in the induction of apoptosis. Lee et al. have now found a role for MKRN1, an E3 ubiquitin ligase that targets p53 and p21, in FADD regulation. Working in HeLa cells, the authors observed that MKRN1 knockdown induced p53-independent cell death and that addition of a pan-caspase inhibitor reversed those effects, suggesting that MRKN1 is involved in caspase-dependent apoptosis. Further experiments revealed faster DISC formation as well as increased FADD levels upon MKRN1 depletion. In addition, MRKN1 directly ubiquitinates FADD, leading to its proteasomal degradation and negatively regulating DR-mediated apoptosis. Interestingly, MRKN1 knockdown also increased formation of the RIP1–RIP3–FADD necrosome complex, but additional depletion of FADD led to even more RIP1–RIP3 complex formation and more efficient necroptoptic cell death in a mouse fibroblast cell line. These data support a negative role for FADD in necroptosis and implicate MKRN1 in an uncharacterized role in this pathway. Overall, the findings suggest that MKRN1 prevents killing of normal cells and may also limit cell death in the presence of a DR signal. (Nat. Commun. 3, 978, 2012)