Abstract :
[en] Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of CLYBL loss of function with reduced circulating vitamin B12 levels was proposed to result from inhibition of the B12-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of CLYBL across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that CLYBL knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B12 deficiency observed in individuals with CLYBL loss of function.
Disciplines :
Biochemistry, biophysics & molecular biology
Human health sciences: Multidisciplinary, general & others
Funding text :
This work was supported by the Luxembourg National Research Fund through an AFR postdoc grant (no. 9180195) to K.W.E. and a PhD fellowship to P.P. within the Doctoral Training Unit ACTIVE (grant no. PRIDE19/14063202/ACTIVE) under the supervision of C.L.L., the University of Luxembourg through Internal Research Project (IRP; project HYMEPI) funding to C.L.L., and the European Union\u2019s Horizon 2020 Research and Innovation Programme through grant no. 814418 (SinFonia) to C.L.L. We thank E. Van Schaftingen, G. Bommer and T. Kitami for fruitful discussions related to this work, in addition to L. Sinkkonen for kindly providing the murine 3T3-L1 preadipocytes. We thank D. Esposito for providing the pDEST527 vector (Addgene plasmid no. 1151) and V. Mootha for providing the P. aeruginosa succinyl-CoA:itaconate CoA transferase (Addgene plasmid no. 111293) and HsCLYBL-FLAG (Addgene plasmid no. 111290) plasmids. Finally, we thank the Luxembourg Centre for Systems Biomedicine Metabolomics and Lipidomics Platform (RRID: SCR_024769) for running metabolomics samples and L. Gallucci and X. Dong for their technical and analytical support.
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