Deacetylation of HSD17B10 by SIRT3 regulates cell growth and cell resistance under oxidative and starvation stresses

Lu Liu,Shuaiyi Chen,Xin Yang,Wei-Guo Zhu,Thomas W Christian,Ya-Ming Hou,Chenxu Ge,Boya Liu,Miao Yu,Junhua Zou,Jianyuan Luo,Mengmeng Ren

doi:10.1038/s41419-020-02763-9

Lu Liu, Shuaiyi Chen + Show 10 more

Open Access

https://doi.org/10.1038/s41419-020-02763-9

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Abstract

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is also involved in mitochondrial tRNA maturation. HSD17B10 missense mutations cause HSD10 mitochondrial disease (HSD10MD). HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction. It has also been implicated to play roles in the development of Alzheimer disease (AD) and tumorigenesis. Here, we found that HSD17B10 is a new substrate of NAD-dependent deacetylase Sirtuin 3 (SIRT3). HSD17B10 is acetylated at lysine residues K79, K99 and K105 by the acetyltransferase CBP, and the acetylation is reversed by SIRT3. HSD17B10 acetylation regulates its enzymatic activity and the formation of mitochondrial RNase P. Furthermore, HSD17B10 acetylation regulates the intracellular functions, affecting cell growth and cell resistance in response to stresses. Our results demonstrated that acetylation is an important regulation mechanism for HSD17B10 and may provide insight into interrupting the development of AD.

Highlights

HSD17B10 plays an important role in mitochondrial fatty acid metabolism
The results showed that GST-Sirtuin 3 (SIRT3) pulled down HSD17B10 (Fig. 1e) and GSTHSD17B10 pulled down SIRT3 (Fig. 1f)
HSD17B10 is a highly conserved gene across a large evolutionary distance, and the missense mutations cause the loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in HSD10 mitochondrial disease (HSD10MD)

Summary

Introduction

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is involved in mitochondrial tRNA maturation. HSD17B10 is an essential subunit of human mitochondrial ribonuclease P (RNase P), a complex involved in mitochondrial tRNA maturation[6]. HSD17B10 plays an important role in mitochondrial tRNA maturation. HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction[13,14,15]. In Alzheimer disease (AD), HSD17B10 activity is inhibited by interacting with intracellular Aβ which may contribute to the neuronal dysfunction associated with AD17

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