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Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid ?-oxidation.


ABSTRACT: Neddylation is a ubiquitination-like pathway that controls cell survival and proliferation by covalently conjugating NEDD8 to lysines in specific substrate proteins. However, the physiological role of neddylation in mammalian metabolism remains elusive, and no mitochondrial targets have been identified. Here, we report that mouse models with liver-specific deficiency of NEDD8 or ubiquitin-like modifier activating enzyme 3 (UBA3), the catalytic subunit of the NEDD8-activating enzyme, exhibit neonatal death with spontaneous fatty liver as well as hepatic cellular senescence. In particular, liver-specific UBA3 deficiency leads to systemic abnormalities similar to glutaric aciduria type II (GA-II), a rare autosomal recessive inherited fatty acid oxidation disorder resulting from defects in mitochondrial electron transfer flavoproteins (ETFs: ETFA and ETFB) or the corresponding ubiquinone oxidoreductase. Neddylation inhibition by various strategies results in decreased protein levels of ETFs in neonatal livers and embryonic hepatocytes. Hepatic neddylation also enhances ETF expression in adult mice and prevents fasting-induced steatosis and mortality. Interestingly, neddylation is active in hepatic mitochondria. ETFs are neddylation substrates, and neddylation stabilizes ETFs by inhibiting their ubiquitination and degradation. Moreover, certain mutations of ETFs found in GA-II patients hinder the neddylation of these substrates. Taken together, our results reveal substrates for neddylation and add insight into GA-II.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC7007566 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid β-oxidation.

Zhang Xueying X   Zhang Yao-Lin YL   Qiu Guihua G   Pian Lili L   Guo Lu L   Cao Huanling H   Liu Jian J   Zhao Yawei Y   Li Xin X   Xu Zhe Z   Huang Xiaofeng X   Huang Jingru J   Dong Jie J   Shen Beifen B   Wang Hong-Xia HX   Ying Xiaomin X   Zhang Weiping J WJ   Cao Xuetao X   Zhang Jiyan J  

Proceedings of the National Academy of Sciences of the United States of America 20200115 5


Neddylation is a ubiquitination-like pathway that controls cell survival and proliferation by covalently conjugating NEDD8 to lysines in specific substrate proteins. However, the physiological role of neddylation in mammalian metabolism remains elusive, and no mitochondrial targets have been identified. Here, we report that mouse models with liver-specific deficiency of NEDD8 or ubiquitin-like modifier activating enzyme 3 (UBA3), the catalytic subunit of the NEDD8-activating enzyme, exhibit neon  ...[more]

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