期刊
CELL REPORTS
卷 29, 期 13, 页码 4407-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.066
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资金
- ATIP-Avenir program of the Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology)
- Agence Nationale de la Recherche (ANR) [ANR-10-IAHU-01, ANR-14-ACHN-0013]
- Fondation pour la Recherche Medicale [FRMSPF20170938629]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [804474]
- Emmy Noether Programme by the German Research Foundation (DFG) [LI1817/2-1]
- collaborative research initiative by the German Research Foundation (DFG) [SFB 1140]
- St. Peter's Trust for Kidney, Bladder, and Prostate Research
- European Research Council (ERC) [804474] Funding Source: European Research Council (ERC)
HNF4A is a nuclear hormone receptor that binds DNA as an obligate homodimer. While all known human heterozygous mutations are associated with the autosomal-dominant diabetes form MODY1, one particular mutation (p.R85W) in the DNA-binding domain (DBD) causes additional renal Fanconi syndrome (FRTS). Here, we find that expression of the conserved fly ortholog dHNF4 harboring the FRTS mutation in Drosophila nephrocytes caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. While the nuclear depletion led to mitochondrial defects and lipid droplet accumulation, the cytosolic aggregates triggered the expansion of the endoplasmic reticulum (ER), autophagy, and eventually cell death. The latter effects could be fully rescued by preventing nuclear export through interfering with serine phosphorylation in the DBD. Our data describe a genomic and a nongenomic mechanism for FRTS in HNF4A-associated MODY1 with important implications for the renal proximal tubule and the regulation of other nuclear hormone receptors.
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