ABIN-1 is a Ubiquitin Sensor that Restricts Cell Death and Sustains Embryonic Development

Proteins that directly regulate TNFR signaling play critical roles in regulating cellular activation and survival. A20 Binding and Inhibitor of NFkB (ABIN-1) is a novel protein that is thought to inhibit NFkB signaling (1, 2). Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to TNF-induced PCD, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD in TNF-induced signaling complexes, preventing caspase 8 cleavage and PCD. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1’s anti-apoptotic activity. These studies provide new insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.