Differential cellular proteomics of human apolipoprotein E (APOE) and determination of its interaction with mitochondria-associated membranes and proteins
Final Report Abstract
Apolipoprotein E (APOE) is best known for its participation in lipid metabolism, but growing interest has emerged in its diverse pleiotropic functions. In this context, APOE is believed to play a central role in the cellular stress response, as its expression is induced under various conditions, including the accumulation of unfolded proteins, proinflammatory activity, and membrane damage. In addition to its secretory role, APOE has been identified in non-secretory compartments, including mitochondria and mitochondria-associated ER membranes (MAM), which are highly dynamic, punctate membrane contacts considered to be a functional entity. The present project focused on the functional analysis of the interaction between APOE and the mitochondrial proteins BCKDHA, LONP1 and TOMM40, a previously unexplored area, potentially revealing novel non-traditional roles for APOE. This main objective has been supported by the quantification of tissue-specific proteomes and proteolytic processing-derived truncated proteoforms, influenced by APOE isoforms and dietary factors. In contrast to the interaction with BCKDHA - which was enhanced under dietary restriction, but not different between the APOE isoforms - LONP1-binding was more pronounced with APOE4 and increased under proteostatic stress. Despite the fact that the insufficient data of the truncated proteoforms analysis prevented a definite conclusion, our results support the assumption that APOE is involved in the metabolic stress adaptation of liver cells. The interaction with mitochondrial proteins is likely facilitated by the accumulation at MAMs, and appears to be individually regulated. Unexpectedly, proteome analyses revealed only a few proteins with APOE isoform-dependent differential abundance across multiple tissues. Overall, valuable fundamental insights have been gained, expanding the understanding of nontraditional roles of APOE while also providing important stimuli for new hypotheses and research projects.
Publications
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Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function. Cellular and Molecular Life Sciences, 79(9).
Rueter, Johanna; Rimbach, Gerald & Huebbe, Patricia
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Allelic variation within the major APOE CpG island affects its methylation in the brain of targeted replacement mice expressing human APOE. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1866(3), 194942.
Rueter, Johanna; Rimbach, Gerald & Huebbe, Patricia
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The mitochondrial BCKD complex interacts with hepatic apolipoprotein E in cultured cells in vitro and mouse livers in vivo. Cellular and Molecular Life Sciences, 80(3).
Rueter, Johanna; Rimbach, Gerald; Treitz, Christian; Schloesser, Anke; Lüersen, Kai; Tholey, Andreas & Huebbe, Patricia
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Human APOE4 Protects High-Fat and High-Sucrose Diet Fed Targeted Replacement Mice against Fatty Liver Disease Compared to APOE3. Aging and disease, 15(1), 259.
Huebbe, Patricia; Bilke, Stephanie; Rueter, Johanna; Schloesser, Anke; Campbel, Graeme; Glüer, Claus-C.; Lucius, Ralph; Röcken, Christoph; Tholey, Andreas & Rimbach, Gerald
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Readdressing the Localization of Apolipoprotein E (APOE) in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes (MAMs): An Investigation of the Hepatic Protein–Protein Interactions of APOE with the Mitochondrial Proteins Lon Protease (LONP1), Mitochondrial Import Receptor Subunit TOM40 (TOMM40) and Voltage-Dependent Anion-Selective Channel 1 (VDAC1). International Journal of Molecular Sciences, 25(19), 10597.
Rueter, Johanna; Rimbach, Gerald; Bilke, Stephanie; Tholey, Andreas & Huebbe, Patricia
