Loss of Trabid,a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1,Reduces Life Span

A relatively unexplored nexus in drosophila immune deficiency (imd) pathway is tgf-beta activating kinase 1 (tak1),which triggers both immunity and apoptosis. in a cell culture screen,we identified that lysine at position 142 was a k63-linked ubiquitin acceptor site for tak1,required for signalling. moreover,lysine at position 156 functioned as a k48-linked ubiquitin acceptor site,also necessary for tak1 activity. the deubiquitinase trabid interacted with tak1,reducing immune signalling output and k63-linked ubiquitination. the three tandem npl4 zinc fingers and the catalytic cysteine at position 518 were required for trabid activity. flies deficient for trabid had a reduced life span due to chronic activation of imd both systemically as well as in their gut where homeostasis was disrupted. the tak1-associated binding protein 2 (tab2) was linked with the tak1-trabid interaction through its zinc finger domain that pacified the tak1 signal. these results indicate an elaborate and multi-tiered mechanism for regulating tak1 activity and modulating its immune signal. © 2014 fernando et al.