Table 2.

Summary of phenotypes in double- and triple-knockout mice ablated for genes that regulate apoptosis, necroptosis, and inflammation.

Crossed mice	ripk1−/−  die postnatal day 1	ripk1−/−  tnfr−/−  die postnatal day 1	sharpin−/−  viable die postnatal days 10–14 inflammation	a20−/−  viable die postnatal days 7–14 inflammation	cyld−/−  viable reach adulthood inflammation
ripk3−/−  casp8−/−  viable	Viable	Viable?	Embryonic  lethal	Embryonic  lethal	?
ripk3−/−  fadd−/−  viable	Viable	Viable?	Embryonic  lethal	Embryonic  lethal	?
ripk3−/−  tnfr−/−  viable	Reach adulthood	Viable?	Prevent inflammation skin dermatitis	Prevent inflammation Cachexia	?
ifnar−/−  viable	Die postnatal day 1	Die later than ripk1−/−  tnfr1−/−	?	?	?
trif−/−  viable	Die postnatal day 1	Die later than ripk1−/−  tnfr1−/−	?	?	?
ripk3−/−  mlkl−/−  die postnatal day 4	Die postnatal day 4	Die later than ripk1−/−  tnfr1−/−	Prevent systemic inflammation	?	?

Summary of phenotypes for double- and triple-knockout mice models of apoptosis, necroptosis, and inflammation genes. Knockout mice for RIPK1, Ripk1−/−, die at birth of systemic inflammation whereas Ripk3−/− mice are normal but are resistant to proinflammatory stimuli. Mlkl−/− mice are anatomically normal, viable, and fertile. Triple-knockout mice Fadd−/− Flip−/− Ripk3−/− have a normal cell-death pathway and develop to normal birth because of absence of necrosis and apoptosis which are modulated by caspase-8. Casp8−/− Mlkl−/− double knockout mice are normal and resistant to TNF-induced necroptosis. Deletion of Tnfr gene provides protection from Ripk1−/− perinatal lethality and double KO mice Ripk1−/− tnfr−/− can be partially protected from lethality from systemic inflammation by mating these mice with ifnar−/− or trif−/− mice. This indicated that both proteins can engage RIPK3-MLKL interaction independent of RIPK1. A20 and CYLD target similar molecular substrates including TRAF2, TRAF6, NF-κB essential modulator (NEMO), and RIPK1. The deubiquitinase CYLD removes the K63-Ub of RIPK1, and A20 promotes the removal of K63-linked ubiquitin chains to terminate signaling induced NF-κB activation. The ablation of A20 and SHARPIN genes is potentially lethal. A20/TNFAIP3, zinc finger and ubiquitin editing protein, CYLD, cylindromatosis, deubiquitylating enzyme; SHARPIN, a protein that together with HOIL-1 and HOIP forms the LUBAC, the heterotrimeric linear ubiquitin chain assembly complex; both are involved in the TNF signaling pathways; IFNAR, the type I IFN receptor. The question mark indicates possible or still unknown phenotype.