The Drosophila AWP1 ortholog Doctor No regulates JAK/STAT signaling for left-right asymmetry in the gut by promoting receptor endocytosis

Many internal Drosophila organs show stereotypical left-right (LR) asymmetry, for which the underlying mechanisms remain elusive. Here, we identified an evolutionarily conserved ubiquitin-binding protein, AWP1/Doctor no (Drn), as a novel factor required for the LR asymmetry of the embryonic anterior gut in Drosophila. We showed that drn is essential in the circular visceral muscle cells of the midgut for JAK/STAT signaling, which contributes to the first known cue for anterior gut lateralization via LR-asymmetric nuclear rearrangement. Embryos homozygous for drn and lacking its maternal contribution showed phenotypes similar to that of depleted JAK/STAT signaling, suggesting that Drn is a general component of JAK/STAT signaling. The absence of Drn resulted in the specific accumulation of Domeless (Dome), the receptor of JAK/STAT signaling, in intracellular compartments. Thus, Drn is required for the endocytic trafficking of Dome, which is subsequently degraded in lysosomes. Our results suggest that the endocytosis of Dome is a critical step in activating JAK/STAT signaling. The roles of AWP1/Drn in activating JAK/STAT signaling and in LR-asymmetric development may be conserved in various organisms. Summary StatementDr. No, a Drosophila ortholog of AWP1, activates JAK/STAT signaling via Dome receptor endocytosis in a crucial step for left-right asymmetry in the developing gut.