Smooth septate junctions (sSJs) prevent the paracellular flow of solutes across the intestinal epithelium of invertebrates. To date, only three specific molecular components of sSJs – the membrane proteins Ssk, Mesh and Tsp2A – have been identified and, thus, the mechanisms of sSJ organization and function are poorly understood. In this work, Yasushi Izumi and colleagues (Izumi et al., 2021) identify and characterise a novel component of sSJs. This protein, called Hoka, colocalises with Mesh at sSJs in the apicolateral region of midgut epithelial cells. In the outer epithelial layer of the proventriculus of stage 15–16 embryos, Hoka associates with sSJs and is required for the localisation of Ssk, Mesh and Tsp2A. The authors show that these proteins are mislocalised in first instar hoka mutant larvae, which leads to disruption of sSJs in the midgut. Interestingly, Hoka co-immunoprecipitates with Ssk, Mesh and Tsp2A, suggesting that these proteins form a complex. In adult enterocytes, depletion of Hoka disrupts the epithelial barrier in the midgut and causes increased proliferation of intestinal stem cells (ISCs), which depends on the activity of aPKC and the Hippo transcriptional activator Yki. Together, these findings identify Hoka as a novel member of an sSJ protein complex that regulates ISC proliferation through aPKC and the Hippo pathway.
