# The Drosophila pseudokinase Tribbles translocates to the fat body membrane in response to fasting to modulate insulin sensitivity

## TL;DR

The Drosophila protein Tribbles moves to the fat body membrane during fasting to reduce insulin sensitivity, and a mutation in its activation loop disrupts this process.

## Contribution

The study reveals how Tribbles translocation to the membrane modulates insulin signaling in response to fasting or reduced insulin signaling.

## Key findings

- Trbl translocates to the plasma membrane during fasting or reduced insulin signaling.
- An E/G mutation in Trbl's activation loop disrupts its function and translocation.
- Increased Akt activity translocates Trbl to the membrane, modulating insulin responses.

## Abstract

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.

Summary: In response to dietary stress, the Drosophila pseudokinase Tribbles (Trib) translocates to the membrane to block Akt activation and mutation of the conserved pseudokinase activation loop dominantly disrupts translocation.