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Caspase-8 is an initiator of death receptor-induced apoptosis and an inhibitor of RIPK3-MLKL-dependent necroptosis. In addition, caspase-8 has been implicated in diseases such as lymphoproliferation, immunodeficiency, and autoimmunity in humans. Although auto-cleavage is indispensable for caspase-8 activation, its physiological functions remain poorly understood. Here, we generated a caspase-8 mutant lacking E385 in auto-cleavage site knock-in mouse ( Casp8   ΔE385/ΔE385  ).  Casp8   ΔE385/ΔE385   cells were expectedly resistant to Fas-induced apoptosis, however,  Casp8  Δ E385/ΔE385   cells could switch TNF-α-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(ΔE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably,  Casp8  Δ E385/ΔE385   Ripk3   −/−   mice partially rescued the perinatal death of  Ripk1   −/−   mice by blocking apoptosis and necroptosis. In contrast to the  Casp8   −/−   Ripk3   −/−   and  Casp8   −/−   Mlkl   −/−   mice appearing autoimmune lymphoproliferative syndrome (ALPS), both  Casp8  Δ E385/ΔE385   Ripk3   −/−   and  Casp8  Δ E385/ΔE385   Mlkl   −/−   mice developed transplantable lymphopenia that could be significantly reversed by RIPK1 heterozygosity, but not by RIPK1 kinase dead mutation. Collectively, these results demonstrate previously unappreciated roles for caspase-8 auto-cleavage in regulating necroptosis and maintaining lymphocytes homeostasis.

Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia