Dataset Information

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

ABSTRACT: Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5-deficiency leads to neutral lipid storage disease in mice. Cardiac-specific gene therapy of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts and murine transgenic ABHD5 expression protects from pressure-overload induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis and enable new translational approaches to treat cardiometabolic disease.

SUBMITTER: Jebessa ZH

PROVIDER: S-EPMC6861130 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Jebessa Zegeye H ZH Shanmukha Kumar D KD Dewenter Matthias M Lehmann Lorenz H LH Xu Chang C Schreiter Friederike F Siede Dominik D Gong Xue-Min XM Worst Barbara C BC Federico Giuseppina G Sauer Sven W SW Fischer Tamas T Wechselberger Lisa L Müller Oliver J OJ Sossalla Samuel S Dieterich Christoph C Most Patrick P Gröne Herrmann-Josef HJ Moro Cedric C Oberer Monika M Haemmerle Guenter G Katus Hugo A HA Tyedmers Jens J Backs Johannes J

Nature metabolism 20191115 11

Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts <i>in vivo</i> and <i>in vitro</i> as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. A ...[more]

PMID: 31742248

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Project description:A critical challenge for all organisms is to carefully control the amount of lipids they store. An important node for this regulation is the protein coat present at the surface of lipid droplets (LDs), the intracellular organelles dedicated to lipid storage. Only limited aspects of this regulation are understood so far. For the probably best characterized case, the regulation of lipolysis in mammals, some of the major protein players have been identified, and it has been established that this process crucially depends on an orchestrated set of protein-protein interactions. Proteomic analysis has revealed that LDs are associated with dozens, if not hundreds, of different proteins, most of them poorly characterized, with even fewer data regarding which of them might physically interact. To comprehensively understand the mechanism of lipid storage regulation, it will likely be essential to define the interactome of LD-associated proteins.Previous studies of such interactions were hampered by technical limitations. Therefore, we have developed a split-luciferase based protein-protein interaction assay and test for interactions among 47 proteins from Drosophila and from mouse. We confirmed previously described interactions and identified many new ones. In 1561 complementation tests, we assayed for interactions among 487 protein pairs of which 92 (19%) resulted in a successful luciferase complementation. These results suggest that a prominent fraction of the LD-associated proteome participates in protein-protein interactions.In targeted experiments, we analyzed the two proteins Jabba and CG9186 in greater detail. Jabba mediates the sequestration of histones to LDs. We successfully applied our split luciferase complementation assay to learn more about this function as we were e.g. able to map the interaction between Jabba and histones. For CG9186, expression levels affect the positioning of LDs. Here, we reveal the ubiquitination of CG9186, and link this posttranslational modification to LD cluster induction.

Dataset Information

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Publications

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.

Similar Datasets

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