Stimulation of death receptors by agonists such as FasL and TNFalpha activates apoptotic
cell death in apoptotic-competent conditions or a type of necrotic cell death dependent
on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genome-wide
siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate
necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1
kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved
in both necroptosis and apoptosis. We show that the expression of subsets of the 432
genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis
is regulated by an extensive signaling network mediating innate immunity. Interestingly,
Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis.
Our study defines a cellular signaling network that regulates necroptosis and the
molecular bifurcation that controls apoptosis and necroptosis.