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Differential functions of ApoER2 and very low density lipoprotein receptor in Reelin signaling depend on differential sorting of the receptors.

ABSTRACT: ApoER2 and very low density lipoprotein (VLDL) receptor transmit the Reelin signal into target cells of the central nervous system. To a certain extent, both receptors can compensate for each other, and only the loss of both receptors results in the reeler phenotype, which is characterized by a gross defect in the architecture of laminated brain structures. Nevertheless, both receptors also have specific distinct functions, as corroborated by analyses of the subtle phenotypes displayed in mice lacking either ApoER2 or VLDL receptor. The differences in their function(s), however, have not been defined at the cellular level. Here, using a panel of chimeric receptors, we demonstrate that endocytosis of Reelin and the fate of the individual receptors upon stimulation are linked to their specific sorting to raft versus non-raft domains of the plasma membrane. VLDL receptor residing in the non-raft domain endocytoses and destines Reelin for degradation via the clathrin-coated pit/clathrin-coated vesicle/endosome pathway without being degraded to a significant extent. Binding of Reelin to ApoER2, a resident of rafts, leads to the production of specific receptor fragments with specific functions of their own and to degradation of ApoER2 via lysosomes. These features contribute to a receptor-specific fine tuning of the Reelin signal, leading to a novel model that emphasizes negative feedback loops specifically mediated by ApoER2 and VLDL receptor, respectively.

SUBMITTER: Duit S

PROVIDER: S-EPMC2836094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sorting nexin 17 regulates ApoER2 recycling and reelin signaling.

Project description:ApoER2 is a member of the low density-lipoprotein receptor (LDL-R) family. As a receptor for reelin, ApoER2 participates in neuronal migration during development as well as synaptic plasticity and survival in the adult brain. A previous yeast two-hybrid screen showed that ApoER2 is a binding partner of sorting nexin 17 (SNX17) - a cytosolic adaptor protein that regulates the trafficking of several membrane proteins in the endosomal pathway, including LRP1, P-selectin and integrins. However, no further studies have been performed to investigate the role of SNX17 in ApoER2 trafficking and function. In this study, we present evidence based on GST pull-down and inmunoprecipitation assays that the cytoplasmic NPxY endocytosis motif of ApoER2 interacts with the FERM domain of SNX17. SNX17 stimulates ApoER2 recycling in different cell lines including neurons without affecting its endocytic rate and also facilitates the transport of ApoER2 from the early endosomes to the recycling endosomes. The reduction of SNX17 was associated with accumulation of an ApoER2 carboxy-terminal fragment (CTF). In addition, in SNX17 knockdown cells, constitutive ApoER2 degradation was not modified, whereas reelin-induced ApoER2 degradation was increased, implying that SNX17 is a regulator of the receptor's half-life. Finally, in SNX17 silenced hippocampal and cortical neurons, we underscored a positive role of this endosomal protein in the development of the dendritic tree and reelin signaling. Overall, these results establish the role of SNX17 in ApoER2 trafficking and function and aid in identifying new links between endocytic trafficking and receptor signaling.

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2024-09-04 | GSE244392 | GEO

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Project description:BackgroundAs the approach to low-density lipoprotein cholesterol (LDL-C) lowering becomes increasingly intensive, accurate assessment of LDL-C at very low levels warrants closer attention in individualized clinical efficacy and safety evaluation. We aimed to assess the accuracy of LDL-C estimation at very low levels by the Friedewald equation, the de facto clinical standard, and compare its accuracy with a novel, big data-derived LDL-C estimate.MethodsIn 191,333 individuals with Friedewald LDL-C < 70 mg/dL, we compared the accuracy of Friedewald and novel LDL-C values in relation to direct measurements by Vertical Auto Profile ultracentrifugation. We examined differences (estimate minus ultracentrifugation) and classification according to levels initiating additional safety precautions per clinical practice guidelines.ResultsFriedewald values were less than ultracentrifugation measurement, with a median difference (25th to 75th percentile) of -2.4 (-7.4 to 0.6) at 50-69 mg/dL, -7.0 (-16.2 to -1.2) at 25-39 mg/dL, and -29.0 (-37.4 to -19.6) at < 15 mg/dL. The respective values by novel estimation were -0.1 (-1.5 to 1.3), -1.1 (-2.5 to 0.3), and -2.7 (-4.9 to 0.0) mg/dL. Among those with Friedewald LDL-C < 15, 15 to < 25, and 25 to < 40 mg/dL, the classification was discordantly low in 94.9%, 82.6%, and 59.9% of individuals as compared with 48.3%, 42.4%, and 22.4% by novel estimation.ConclusionsEstimation of even lower LDL-C values (by Friedewald and novel methods) is even more inaccurate. More often than not, a Friedewald value < 40 mg/dL is underestimated, which translates into unnecessary safety alarms that could be reduced in half by estimation using our novel method.

| S-EPMC5399386 | biostudies-literature

The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.

Project description:We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.

| S-EPMC2888382 | biostudies-literature

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