Activated \u03b12-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal M\xfcller Glial Cells

Javier R Jaldín-Fincati,María C Sánchez,Nicolás M Díaz,Virginia Actis Dato,Gustavo A Chiabrando,Pablo F Barcelona

doi:10.1038/s41598-019-49072-6

Abstract

Activated α2-macroglobulin (α2M*) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have been linked to proliferative retinal diseases. In Müller glial cells (MGCs), the α2M*/LRP1 interaction induces cell signaling, cell migration, and extracellular matrix remodeling, processes closely associated with proliferative disorders. However, the mechanism whereby α2M* and LRP1 participate in the aforementioned pathologies remains incompletely elucidated. Here, we investigate whether α2M* regulates both the intracellular distribution and sorting of LRP1 to the plasma membrane (PM) and how this regulation is involved in the cell migration of MGCs. Using a human Müller glial-derived cell line, MIO-M1, we demonstrate that the α2M*/LRP1 complex is internalized and rapidly reaches early endosomes. Afterward, α2M* is routed to degradative compartments, while LRP1 is accumulated at the PM through a Rab10-dependent exocytic pathway regulated by PI3K/Akt. Interestingly, Rab10 knockdown reduces both LRP1 accumulation at the PM and cell migration of MIO-M1 cells induced by α2M*. Given the importance of MGCs in the maintenance of retinal homeostasis, unravelling this molecular mechanism can potentially provide new therapeutic targets for the treatment of proliferative retinopathies.

Highlights

Www.nature.com/scientificreports retina can be severely injured, which may culminate in neovascularization, vitreous hemorrhage, and mechanical damage such as retinal detachment[7]
Considering all the above, we investigate whether α2M* regulates both the intracellular distribution and sorting of lipoprotein receptor-related protein 1 (LRP1) to the plasma membrane (PM) and the molecular mechanisms whereby this regulation is involved in the cell migration of Moorfields/Institute of Ophthalmology-Muller 1 (MIO-M1) cells
We characterize the molecular mechanism responsible for LRP1 sorting to the PM upon α2M* stimulation and how this biological process impinges on Müller glial cells (MGCs) migration

Summary

Introduction

Www.nature.com/scientificreports retina can be severely injured, which may culminate in neovascularization, vitreous hemorrhage, and mechanical damage such as retinal detachment[7]. It has been described that the α2M*/LRP1 interaction, in spite of inducing endocytosis of the inhibitor-protease complex, activates different intracellular signaling pathways in numerous cell types, including macrophages[8,9,10,11], Schwann cells[12], and Müller glial cells (MGCs)[13]. In this regard, we have previously demonstrated that α2M* promotes MGCs migration by regulating the matrix metalloproteinases (MMPs) activity through LRP114. Results α2M* induces LRP1 accumulation in early, but not in late endosomes or acidic/degradative compartments of MIO-M1 cells

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Methods

Conclusion