Abstract
Energy homeostasis is crucial for maintaining normally functioning cells; disturbances in this balance often cause various diseases. The limb region 1 (LMBR1) domain containing 1 gene (lmbrd1) encodes the LMBD1 protein that possesses 9 putative transmembrane domains. LMBD1 has been suggested to be involved in the lysosome in aiding the export of cobalamin. In this study, we determined that LMBD1 plays a regulatory role in the plasma membrane. A micro-positron emission tomography analysis showed that a single-allele knock-out of lmbrd1 increased the (18)F-fluorodeoxyglucose uptake in murine hearts. In addition, the knockdown of lmbrd1 resulted in an up-regulated signaling of the insulin receptor (IR) and its downstream signaling molecule, Akt. Confocal and live total internal reflection fluorescence microscopy showed that LMBD1 co-localized and co-internalized with clathrin and the IR, but not with the transferrin receptor. The results of the mutation analysis and phenotypic rescue experiments indicate that LMBD1 interacts with adaptor protein-2 and is involved in the unique clathrin-mediated endocytosis of the IR. LMBD1 selectively interacts with the IR. The knockdown of lmbrd1 attenuated IR endocytosis, resulting in the perturbation of the IR recycling pathway and consequential enhancement of the IR signaling cascade. In summary, LMBD1 plays an imperative role in mediating and regulating the endocytosis of the IR.
Highlights
LMBD1 is a transmembrane protein encoded by the lmbrd1 gene
Additional studies should elucidate the mechanisms by which LMBD1 interacts with the insulin receptor (IR) and the stoichiometric ratio required for LMBD1 to participate in the endocytosis process
Previous studies have demonstrated that in Adaptor protein-2 (AP-2)-depleted cells and in transferrin receptor trafficking protein (TTP)-deficient cells, the clathrin-mediated endocytosis of transferrin receptor (TrfR) was severely hindered [14, 30], suggesting that both components are critical in the TrfR endocytotic process
Summary
LMBD1 is a transmembrane protein encoded by the lmbrd gene. Its biological function remains unclear. Results: lmbrd knockdown hinders the internalization of the insulin receptor, allowing it and its downstream signaling molecules to remain activated. Clathrin-mediated endocytosis is a major pathway for receptor internalization, which is essential for both the recycling of proteins and receptors on the PM and the intracellular signaling [7]. Incorporation of the transmembrane cargoes into the clathrin-coated pits requires the cargo proteins to contain specific adaptor protein recognition motifs, such as the YXX⌽ motif being recognized by the 2 subunit of AP-2, a process that has been shown to be meticulously governed. The transferrin receptor (TrfR), an AP-2 cargo that possesses the YXX⌽ motif, was found to be selectively internalized through its cargo-specific adaptor, the transferrin receptor trafficking protein (TTP) [14]. We determined that PM-localized LMBD1 functions as a specific adaptor for the clathrin-mediated endocytosis of the IR
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