The <i>Drosophila</i> pseudokinase Tribbles translocates to the fat body membrane in response to fasting to modulate insulin sensitivity

The Drosophila pseudokinase Tribbles (Trbl) shares conserved functions with human TRIB3 to bind and inhibit Akt phosphorylation-activation by the Insulin Receptor (InR) to reduce insulin responses; consistent with this, increased levels of human TRIB3 are linked to type 2 diabetes. Here, we show that in fat body cells of well-fed Drosophila larvae, Trbl expression is low and predominantly in the nucleus while fasting or genetic reduction of insulin signaling resulted in increased Trbl expression and Trbl protein translocation to the plasma membrane. An E/G mutation in the Trbl pseudokinase kinase activation loop dominantly interfered with Trbl function leading to increased Akt activity, increased stability of Trbl substrates, including Trbl itself, and aberrant redistribution of Trbl multimers to the membrane. Several strategies designed to increase Akt activity were sufficient to translocate Trbl to the membrane, consistent with the notion that subcellular trafficking of Trbl to the fat body cell membrane acts a rheostat to reduce the strength of Akt-mediated insulin responses, counter to the InR, which has been shown to redistribute away from the membrane to modulate insulin signaling.