HNF4A is a nuclear hormone receptor that bindsDNA as an obligate homodimer. While all known hu-man heterozygous mutations are associated with theautosomal-dominant diabetes form MODY1, oneparticular mutation (p.R85W) in the DNA-bindingdomain (DBD) causes additional renal Fanconi syn-drome (FRTS). Here, we find that expression of theconserved fly ortholog dHNF4 harboring the FRTSmutation inDrosophilanephrocytes caused nucleardepletion and cytosolic aggregation of a wild-typedHNF4 reporter protein. While the nuclear depletionled to mitochondrial defects and lipid droplet accu-mulation, the cytosolic aggregates triggered theexpansion of the endoplasmic reticulum (ER), auto-phagy, and eventually cell death. The latter effectscould be fully rescued by preventing nuclear exportthrough interfering with serine phosphorylation inthe DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associatedMODY1 with important implications for the renalproximal tubule and the regulation of other nuclearhormone receptors.