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ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development

2008; Nature Portfolio; Volume: 457; Issue: 7231 Linguagem: Inglês

10.1038/nature07575

1476-4687

Shigeru Oshima, Emre E. Turer, Joseph A. Callahan, Sophia Chai, Rommel Advincula, Julio Barrera, Nataliya Tovbis Shifrin, Bettina Lee, Benjamin Yen, Tammy T. Woo, Barbara A. Malynn, Averil Ma,

Immune Response and Inflammation

Oshima et al. this week show that ABIN-1 — a protein that interacts with the ubiquitin-editing enzyme A20 and is thought to negatively influence NF-κB signalling — is essential for life; without it, mice die during embryogenesis with fetal liver apoptosis and anaemia. However, this phenomenon appears unrelated to ABIN-1's role in NF-κB signalling. The authors show that ABIN-1 is ubiquitinated and as such binds to and interferes with components of the TNF-induced signalling complex, the so-called DISC. This prevents programmed cell death and allows proper development. This adds to the emerging role for non-degrading ubiquitin modifications in life and death cell-fate decisions. It is shown that ABIN-1 (a protein that interacts with the ubiquitin-editing enzyme A20 and is thought to negatively influence NF-κB signalling) is essential for life; without it, mice die during embryogenesis with fetal liver apoptosis and anaemia. This appears unrelated to the role of ABIN-1 in NF-κB signalling. Proteins that directly regulate tumour necrosis factor receptor (TNFR) signalling have critical roles in regulating cellular activation and survival. ABIN-1 (A20 binding and inhibitor of NF-κB) is a novel protein that is thought to inhibit NF-κB signalling1,2. Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anaemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to tumour necrosis factor (TNF)-induced programmed cell death, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD (Fas-associated death domain-containing protein) in TNF-induced signalling complexes, preventing caspase 8 cleavage and programmed cell death. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1's anti-apoptotic activity. These studies provide insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.