Post-translational Modifications by SIRT3 De-2-hydroxyisobutyrylase Activity Regulate Glycolysis and Enable Nephrogenesis

Overview

Journal Sci Rep

Specialty Science

Date 2021 Dec 9

PMID 34880332

Citations 9

Authors

Luca Perico

Marina Morigi

Anna Pezzotta

Daniela Corna

Valerio Brizi

Sara Conti

Cristina Zanchi

Fabio Sangalli

Piera Trionfini

Sara Butto

Christodoulos Xinaris

Susanna Tomasoni

Carlamaria Zoja

Giuseppe Remuzzi

Ariela Benigni

Barbara Imberti

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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