In:
Cell Death & Differentiation, Springer Science and Business Media LLC, Vol. 29, No. 8 ( 2022-08), p. 1500-1512
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1350-9047
,
1476-5403
DOI:
10.1038/s41418-022-00938-9
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
1496681-5
SSG:
12
