Scientists in the MRC Protein Phosphorylation Unit have discovered that a polyubiquitin-binding protein called ABIN1 plays a key role in preventing autoimmune disease and their findings were published on line on 23 May 2011 in the Journal of Experimental Medicine and will appear in the June 6th issue of the journal.
Sambit Nanda, a postdoc working in Philip Cohen's research team, studied a mouse line developed in the Institute in which wild type ABIN1 was replaced by a mutant in which the aspartyl residue at position 485 was converted to asparagine, which prevents ABIN1 from binding to Lys63-linked or linear polyubiquitin chains. The mutant mice progressively developed an autoimmune disease that had all the hallmarks of human lupus. Sambit went on to show that immune cells from the mice produced elevated levels of proinflammatory cytokines in response to ligands that activate Toll-Like receptors (TLRs), and proved that the hyperactivation of TLRs was the cause of the autoimmune disease by showing that autoimmunity could be prevented by crossing to mice that do not express MyD88, an adaptor protein essential for TLR function. The study establishes that the binding of polyubiquitin to ABIN1 is required for this protein to limit the strength of TLR signaling in vivo. More detailed analysis of TLR signaling pathways indicates that ABIN1 exerts its effects between MyD88 and the activation of a protein kinase, termed TAK1. Further studies are underway to elucidate the underlying molecular mechanism.
Over the past couple of years polymorphisms in ABIN1 have been discovered in several human populations which predispose to autoimmune diseases, such as lupus and psoriasis. This suggests that the mouse line developed in this study may be a good model for human autoimmune diseases and be valuable in testing the efficacy of new drugs to treat autoimmunity, which exert their effects by targeting components of TLR signaling pathways.
Sambit Nanda, a postdoc working in Philip Cohen's research team, studied a mouse line developed in the Institute in which wild type ABIN1 was replaced by a mutant in which the aspartyl residue at position 485 was converted to asparagine, which prevents ABIN1 from binding to Lys63-linked or linear polyubiquitin chains. The mutant mice progressively developed an autoimmune disease that had all the hallmarks of human lupus. Sambit went on to show that immune cells from the mice produced elevated levels of proinflammatory cytokines in response to ligands that activate Toll-Like receptors (TLRs), and proved that the hyperactivation of TLRs was the cause of the autoimmune disease by showing that autoimmunity could be prevented by crossing to mice that do not express MyD88, an adaptor protein essential for TLR function. The study establishes that the binding of polyubiquitin to ABIN1 is required for this protein to limit the strength of TLR signaling in vivo. More detailed analysis of TLR signaling pathways indicates that ABIN1 exerts its effects between MyD88 and the activation of a protein kinase, termed TAK1. Further studies are underway to elucidate the underlying molecular mechanism.
Over the past couple of years polymorphisms in ABIN1 have been discovered in several human populations which predispose to autoimmune diseases, such as lupus and psoriasis. This suggests that the mouse line developed in this study may be a good model for human autoimmune diseases and be valuable in testing the efficacy of new drugs to treat autoimmunity, which exert their effects by targeting components of TLR signaling pathways.