Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease

Abstract

Lipoylation is a rare, but highly conserved lysine posttranslational modification. To date, it is known to occur on only four multimeric metabolic enzymes in mammals, yet these proteins are staples in the core metabolic landscape. The dysregulation of these mitochondrial proteins is linked to a range of human metabolic disorders. Perhaps most striking is that lipoylation itself, the proteins that add or remove the modification, as well as the proteins it decorates are all evolutionarily conserved from bacteria to humans, highlighting the importance of this essential cofactor. Here, we discuss the biological significance of protein lipoylation, the importance of understanding its regulation in health and disease states, and the advances in mass spectrometry-based proteomic technologies that can aid these studies.

Overexpressing the H‐protein of the glycine cleavage system increases biomass yield in glasshouse and field‐grown transgenic tobacco plants

“…Lipoylation is a post-translational modification essential for the activity of a number of multimeric metabolic complexes including the GCS, through the H-protein (Douce et al, 2001), and the E2 subunits of the enzymatic complexes PDH and KDH which are critical in regulating distinct carbon entry points into the central metabolic pathway of the tricarboxylic acid cycle (Rowland et al, 2018). In both the ST-LS1::H and 35S:::H OX plants, the lipoylation signal corresponding to the H-protein is increased, which is consistent with an increased amount of this protein in the leaves of these plants.…”

Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis

“…Lipoate is the conjugate base of lipoic acid that functions as an essential co-factor for the activity of several mitochondrial enzymes, including DLAT in the PDH complex, DBT in the branched-chain oxoacid dehydrogenase (BCDH) complex, and DLST in alphaketoglutarate dehydrogenase (KGDH) 27 . Since lipoylated proteins and their protein complex in BAT remain uncharacterized, we next immunopurified endogenous lipoylated proteins from iBAT and identified them by liquid chromatography-mass spectrometry (LC-MS/MS) ( Figure 2d).…”

CRISPR screens in physiologic medium reveal conditionally essential genes in human cells

“…The conditional essentiality analysis also revealed hits involved in the transport of various metabolites (SLC25A1, SLC25A11, and SLC7A1), small ions (SLC25A37 and SLC20A1), or even an unknown substrate (SLC25A46) ( Figure 2G). Genes involved in lipoylation, a posttranslational attachment of lipoamide to proteins, were identified as HPLM-essential hits, while others that encode components of the UFMylation machinery, a system that attaches UFM1 to proteins, instead scored as RPMI-essential ( Figure 2H) (Komatsu et al, 2004;Rowland et al, 2018;Solmonson and DeBerardinis, 2018;Wang et al, 2017). Additional genes with strong mediumdependent phenotypes are involved in protein catabolism, including components of the ClpXP protease complex (CLPX and CLPP) and of E3 ubiquitin-protein ligase complexes (KCTD10 and FBXW11), as well as in RNA processing (YBEY, LSM1, and PAPD5), apoptosis (BCL2L1, PARL, and GHITM), and the mTOR pathway (FLCN and FNIP1) (Tsun et al, 2013), among other processes (Figures 2I,2J,and 2K).…”