Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis

• Published in: Scientific reports Vol. 11; no. 1; p. 23580
• Main Authors: Perico, Luca, Morigi, Marina, Pezzotta, Anna, Corna, Daniela, Brizi, Valerio, Conti, Sara, Zanchi, Cristina, Sangalli, Fabio, Trionfini, Piera, Buttò, Sara, Xinaris, Christodoulos, Tomasoni, Susanna, Zoja, Carlamaria, Remuzzi, Giuseppe, Benigni, Ariela, Imberti, Barbara
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/136; 631/136/2060; 631/136/334; Animals; Cell Differentiation - genetics; Cell Nucleus - genetics; Cell self-renewal; Chromatin; Chromatin - genetics; Embryogenesis; Epigenesis, Genetic - genetics; Epigenetics; Glycolysis; Glycolysis - genetics; Histones; Humanities and Social Sciences; Kidney - physiology; Kidney Diseases - genetics; Kidneys; Lysine; Lysine - genetics; Mice; Mice, Inbred C57BL; multidisciplinary; NAD; NAD - genetics; Nephrons; Nephrons - physiology; Organogenesis - genetics; Phosphofructokinase; Phosphofructokinases - genetics; Post-translation; Protein Processing, Post-Translational - genetics; Science; Science (multidisciplinary); Sirtuin 3 - genetics; Sirtuins
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-03039-8

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.