Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Abstract

Endocytosis and intracellular sorting of transforming growth factor-β (TGF-β) receptors play an important regulatory role in TGF-β signaling. Two major endocytic pathways, clathrin-and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors. In this study, we demonstrate that the clathrin-and caveolae-mediated endocytic pathways can converge during TGF-β receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-β type I receptor (TβRI), we found that after mediating TβRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TβRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-β signaling and TGF-β receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-β receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-β receptors.

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

“…Notably, non-canonical autophagy shares components with clearance phagocytosis pathways (53,54). Recent studies have demonstrated the importance of caveolin-1 in multifunctional endosomal and lysosomal compartments (21,55). Our results extend these observations, showing that phagosomes are regulated by caveolin-1 as well.…”

“…Caveolins regulate cellular processes by recruiting protein complexes either on the inner leaflet of the plasma membrane or on cytoplasmic organelles (18 -20). Interestingly, caveolin-1 on a subset of early endosomes has recently been suggested to influence the fate and signaling of internalized TGF-␤ receptors, suggesting that vesicular caveolin-1 may alter vesicle functionality (21). Here we explore mice manipulated to lack caveolin-1 specifically and solely in the RPE.…”

Intracellular trafficking of transforming growth factor β receptors

“…Accordingly, internalized TGFβ receptors were found to be located in EE for extended periods [9,20,21,35,56,66]. Clathrinmediated endocytosis is the fastest internalization pathway [70].…”

“…It has been shown that TGFβ receptors located in lipid rafts are internalized through caveolin-dependent pathways [21,[64][65][66] (Fig. 1).…”

Tissue damage negatively regulates LPS-induced macrophage necroptosis

“…21 Caveolin-1-mediated internalization of multiple cell surface receptors is also known to critically regulate receptor signaling. 22 In this study, we investigated the mechanisms and role of trauma/tissue damage in the regulation of LPS-induced Mϕ necroptosis using a validated mouse model that simulates…”