Lukas Kühn

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Lukas Kühn graduated in biochemistry at the Swiss Federal Institute of Technology in Zürich. He received his PhD in 1979 for a thesis with Jean-Pierre Kraehenbuhl at the University of Lausanne. After postdoctoral work in Lausanne and with Frank Ruddle at Yale University, USA, he became group leader at ISREC in 1984, was promoted senior scientist in 1988 and EPFL Adjunct Professor (professeur titulaire) in June 2008.

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https://people.epfl.ch/lukas.kuehn?lang=fr

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Regulation of mRNA stability by RNA-protein interactions contributes significantly to quantitative aspects of gene expression. We have identified potential mRNA targets of the AU-rich element binding protein AUF1. Myc-tagged AUF1 p42 was induced in mouse NIH/3T3 cells and RNA-protein complexes isolated using anti-myc tag antibody beads. Bound mRNAs were analyzed with Affymetrix microarrays. We have identified 508 potential target mRNAs that were at least 3-fold enriched compared to control cells without myc-AUF1. 22.3% of the enriched mRNAs had an AU-rich cluster in the ARED Organism database, against 16.3% of non-enriched control mRNAs. The enrichment towards AU-rich elements was also visible by AREScore with an average value of 5.2 in the enriched mRNAs versus 4.2 in the control group. Yet, numerous mRNAs were enriched without a high ARE score. The enrichment of tetrameric and pentameric sequences suggests a broad AUF1 p42-binding spectrum at short U-rich sequences flanked by A or G. Still, some enriched mRNAs were highly unstable, as those of TNFSF11 (known as RANKL), KLF10, HES1, CCNT2, SMAD6, and BCL6. We have mapped some of the instability determinants. HES1 mRNA appeared to have a coding region determinant. Detailed analysis of the RANKL and BCL6 3'UTR revealed for both that full instability required two elements, which are conserved in evolution. In RANKL mRNA both elements are AU-rich and separated by 30 bases, while in BCL6 mRNA one is AU-rich and 60 bases from a non AU-rich element that potentially forms a stem-loop structure.

PUBLIC LIBRARY SCIENCE2018

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Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Lukas Kühn

Ferritin plays a central role in iron metabolism and is made of 24 subunits of 2 types: heavy chain and light chain. The ferritin heavy chain (FtH) has ferroxidase activity that is required for iron incorporation and limiting toxicity. The purpose of this study was to investigate the role of FtH in acute kidney injury (AM) and renal iron handling by using proximal tubule-specific FtH-knockout mice (FtHPT(-/-) mice). FtHPT(-/-) mice had significant mortality, worse structural and functional renal injury, and increased levels of apoptosis in rhabdomyolysis and cisplatin-induced AM, despite significantly higher expression of heme oxygenase-1, an antioxidant and cytoprotective enzyme. 'While expression of divalent metal transporter-1 was unaffected, expression of ferroportin (FPN) was significantly lower under both basal and rhabd.omyolysis-induced AM in FtHPT(-/-) mice. Apical localization of FPN was disrupted after AM to a diffuse cytosolic and basolateral pattern. FtH, regardless ofiron content and ferroxidase activity, induced FPN. Interestingly, urinary levels of the iron acceptor proteins neutrophil gelatihase-associated lipocalin, hemopexin, and transferrin were increased in FtHPT(-/-) mice after AM. These results underscore the protective role of FtH and reveal the critical role of proximal tubule FtH in iron trafficking in AM.

American Society for Clinical Investigation2013

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Intestinal ferritin H is required for an accurate control of iron absorption

Lukas Kühn, Liviu Vanoaica

To maintain appropriate body iron levels, iron absorption by the proximal duodenum is thought to be controlled by hepcidin, a polypeptide secreted by hepatocytes in response to high serum iron. Hepcidin limits basolateral iron efflux from the duodenal epithelium by binding and downregulating the intestinal iron exporter ferroportin. Here, we found that mice with an intestinal ferritin H gene deletion show increased body iron stores and transferrin saturation. As expected for iron-loaded animals, the ferritin H-deleted mice showed induced liver hepcidin mRNA levels and reduced duodenal expression of DMT1 and DcytB mRNA. In spite of these feedback controls, intestinal ferroportin protein and Fe-59 absorption were increased more than 2-fold in the deleted mice. Our results demonstrate that hepcidin-mediated regulation alone is insufficient to restrict iron absorption and that intestinal ferritin H is also required to limit iron efflux from intestinal cells.

Elsevier2010

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