Human ZBP1 Is a Potent Inducer of RIPK1-Dependent Cell Death Through Mechanisms Divergent from Mouse ZBP1 [mouse]

While the regulatory mechanisms of mouse ZBP1 (mZBP1) have been well studied, the pathways governing human ZBP1 (hZBP1) remain poorly understood. In this study, we show that unlike mZBP1, overexpression of hZBP1 induces spontaneous cell death in human cell lines.

This response involves activation of both FADD–caspase-8-mediated apoptosis and RIPK3–MLKL-dependent necroptosis. Notably, in contrast to mZBP1, which signals primarily through RIPK3, hZBP1-induced cell death depends on the scaffold function of RIPK1 but not its kinase activity. Importantly, this hZBP1-RIPK1 engagement occurs independently of RIPK3.