GRP94, the endoplasmic reticulum Hsp90, is a metazoan-restricted chaperone essential for early development in mammals, yet dispensable for mammalian cell viability. This dichotomy suggests that GRP94 is required for the functional expression of secretory and/or membrane proteins that enable the integration of cells into tissues. To explore this hypothesis, we have identified the Drosophila ortholog of GRP94, Gp93, and report that Gp93 is an essential gene in Drosophila. Loss of zygotic Gp93 expression is late larval-lethal and causes prominent defects in the larval midgut, the sole endoderm-derived larval tissue. Gp93 mutant larvae display pronounced defects in the midgut epithelium, with aberrant copper cell structure, markedly reduced gut acidification, atypical septate junction structure, depressed gut motility, and deficits in intestinal nutrient uptake. The metabolic consequences of the loss of Gp93-expression are profound; Gp93 mutant larvae exhibit a starvation-like metabolic phenotype, including suppression of insulin signaling and extensive mobilization of amino acids and triglycerides. The defects in copper cell structure/function accompanying loss of Gp93 expression resemble those reported for mutations in labial, an endodermal homeotic gene required for copper cell specification, and α-spectrin, thus suggesting an essential role for Gp93 in the functional expression of secretory/integral membrane protein-encoding lab protein target genes and/or integral membrane protein(s) that interact with the spectrin cytoskeleton to confer epithelial membrane specialization.
