Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice
Zhang, Yuan (Tongji University School of Medicine)
Chen, Yuling (Fudan University)
Zhang, Zhao (Fudan University Shanghai Medical College)
Tao, Xiang (Fudan University)
Xu, Sha (Fudan University)
Zhang, Xinyan (Fudan University)
Zurashvili, Tinatin (David Tvildiani Medical University)
Lu, Zhouping (Tongji University School of Medicine)
Bayascas Ramírez, José Ramón (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Jin, Liping (Tongji University School of Medicine)
Zhao, Jianyuan (Xinhua Hospital School of Medicine)
Zhou, Xiangyu (Fudan University)
Universitat Autònoma de Barcelona. Institut de Neurociències

Fecha:	2022
Resumen:	Acyl-CoA oxidase 2 (Acox2) is an enzyme involved in peroxisomal bile acid synthesis and branched-chain fatty acid degradation. Acox2 knockout (-/-) mice spontaneously developed liver cancer with marked lymphocytic infiltrate. Tandem-affinity purification coupled with mass spectrometry analysis revealed that Acox2 interacted with methylcrotonoyl-CoA carboxylase followed by co-immunoprecipitation confirmation. Here we reported that non-histone lysine crotonylation (Kcr) levels were downregulated in Acox2 -/- mice livers. Interestingly, Kcr signals were concentrated in the nucleus of tumor cells but mostly located in the cytoplasm of adjacent normal liver cells of Acox2 -/- mice. Quantitative analysis of the global crotonylome further revealed that 54% (27/50) of downregulated non-histone Kcr sites were located in mitochondrial (11/50) and peroxisomal (17/50) enzymes including Ehhadh, Scp2, Hsd17b4, Crot, Etfa, Cpt1a, Eci1/2, Hadha, Etfdh, and Idh2. Subsequent site-directed mutagenesis and transcriptome analysis revealed that Ehhadh K 572 cr might have site-specific regulatory roles by downregulating TOP3B expression that lead to increased DNA damage in vitro. Our findings suggested Acox2 is a regulator of Kcr that might play critical role on hepatic metabolic homeostasis.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Metabolic disorders ; Post-translational modifications
Publicado en:	Cell death and disease, Vol. 13 (march 2022) , ISSN 2041-4889

DOI: 10.1038/s41419-022-04725-9
PMID: 35351852

14 p, 7.0 MB

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