Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis
| Autor: | Luca Perico, Marina Morigi, Anna Pezzotta, Daniela Corna, Valerio Brizi, Sara Conti, Cristina Zanchi, Fabio Sangalli, Piera Trionfini, Sara Buttò, Christodoulos Xinaris, Susanna Tomasoni, Carlamaria Zoja, Giuseppe Remuzzi, Ariela Benigni, Barbara Imberti |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Organogenesis
Science Kidney Article Epigenesis Genetic Mice Sirtuin 3 Developmental biology Animals Cell Nucleus Multidisciplinary urogenital system Lysine Cell Differentiation Nephrons NAD Chromatin Mice Inbred C57BL Phosphofructokinases Medicine Kidney Diseases Experimental organisms Glycolysis Protein Processing Post-Translational |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-18 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt3 deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape in Sirt3−/− metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes. |
| Databáze: | OpenAIRE |
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