ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Lynn Verstrepen , Isabelle Carpentier , Kelly Verhelst , Rudi Beyaert

ABINs have been described as three different proteins (ABIN-1, ABIN-2, ABIN-3) that bind the ubiquitin-editing nuclear factor-κB (NF-κB) inhibitor protein A20 and which show limited sequence homology. Overexpression of ABINs inhibits NF-κB activation by tumor necrosis factor (TNF) and several other stimuli. Similar to A20, ABIN-1 and ABIN-3 expression is NF-κB dependent, implicating a potential role for the A20/ABIN complex in the negative feedback regulation of NF-κB activation. Adenoviral gene transfer of ABIN-1 has been shown to reduce NF-κB activation in mouse liver and lungs. However, ABIN-1 as well as ABIN-2 deficient mice exhibit only slightly increased or normal NF-κB activation, respectively, possibly reflecting redundant NF-κB inhibitory activities of multiple ABINs. Other functions of ABINs might be non-redundant. For example, ABIN-1 shares with A20 the ability to inhibit TNF-induced apoptosis and as a result ABIN-1 deficient mice die during embryogenesis due to TNF-dependent fetal liver apoptosis. On the other hand, ABIN-2 is required for optimal TPL-2 dependent extracellularly regulated kinase activation in macrophages treated with TNF or Toll-like receptor ligands. ABINs have recently been shown to contain an ubiquitin-binding domain that is essential for their NF-κB inhibitory and anti-apoptotic activities. In this context, ABINs were proposed to function as adaptors between ubiquitinated proteins and other regulatory proteins. Alternatively, ABINs might disrupt signaling complexes by competing with other ubiquitin-binding proteins for the binding to specific ubiquitinated targets. Altogether, these findings implicate an important role for ABINs in the regulation of immunity and tissue homeostasis.

Mots clés: Inflammation; NF-κB; Apoptosis; ABIN; A20

Lynn Verstrepen, Isabelle Carpentier, Kelly Verhelst, Rudi Beyaert. ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling. Biochemical Pharmacology, 2009, 78 (2), pp.105. ⟨10.1016/j.bcp.2009.02.009⟩. ⟨hal-00493493⟩