| First Author | Li X | Year | 2022 |
| Journal | Cell Death Differ | Volume | 29 |
| Issue | 8 | Pages | 1500-1512 |
| PubMed ID | 35064213 | Mgi Jnum | J:342732 |
| Mgi Id | MGI:7328343 | Doi | 10.1038/s41418-022-00938-9 |
| Citation | Li X, et al. (2022) Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia. Cell Death Differ 29(8):1500-1512 |
| abstractText | 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(DeltaE385/DeltaE385)). Casp8(DeltaE385/DeltaE385) cells were expectedly resistant to Fas-induced apoptosis, however, Casp8(DeltaE385/DeltaE385) cells could switch TNF-alpha-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(DeltaE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8(DeltaE385/DeltaE385)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(DeltaE385/DeltaE385)Ripk3(-/-) and Casp8(DeltaE385/DeltaE385)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. |
