Degradation of AP2 During Reticulocyte Maturation Enhances Binding of Hsc70 and Alix to a Common Site on TfR for Sorting into Exosomes

Géminard, Charles; Gassart, Aude De; Blanc, Lionel; Vidal, Michel

doi:10.1111/j.1600-0854.2004.0167.x

Cited by 182 publications

(152 citation statements)

References 44 publications

(58 reference statements)

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“…We noted that knockdown of PDCD6IP resulted in a significant decrease of GPRC5B-HA in the exosome fraction (Fig. 2), confirming the requirement of PDCD6IP for exosome biogenesis (23,37) and demonstrating the utility of our siRNA-mediated knockdown screening strategy that focused on urinary exosome components.…”

Section: An Rnai Candidate-based Screen For Regulators Of Exosomalsupporting

confidence: 49%

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

Kwon

Nacke

et al. 2016

Journal of Biological Chemistry

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Edited by Thomas SöllnerExosomes, 40 -150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to-endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively.

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Section: An Rnai Candidate-based Screen For Regulators Of Exosomalsupporting

confidence: 49%

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

Kwon

Nacke

et al. 2016

Journal of Biological Chemistry

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“…From previous studies by others, it is known that Hsc70 interacts with the tail region of TfR1 in exosomes (50,51). Also, Hsc70 is known to interact with the cytosolic domain of the TfR1 through the 20 YTRFSLARQV 29 (amino acids 20 -29 in TfR1) (52). It is well documented that Hsc70 mediates transport of proteins and organelles to autophagosomes via interaction with target proteins containing a KFERQ motif (53,54) that can vary considerably in primary sequence.…”

Section: Discussionmentioning

confidence: 99%

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Cao

Schroeder

Chen

et al. 2016

Journal of Biological Chemistry

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Clathrin-mediated endocytosis of transferrin (Tf) and its cognate receptor (TfR1) is a central pathway supporting the uptake of trophic iron. It has generally been assumed that this is a constitutive process. However, we have reported that the non-receptor tyrosine kinase, Src, is activated by Tf to facilitate the internalization of the Tf-TfR1 ligand-receptor complex. As an extension of these findings, we have tested whether subsequent trafficking steps might be regulated by additional kinase-dependent cascades, and we observed a significant endocytic block by inhibiting c-Abl kinase by a variety of methods. Importantly, Tf internalization was reduced significantly in all of these cell models and could be restored by re-expression of WT c-Abl. Surprisingly, this attenuated Tf-TfR1 endocytosis was due to a substantial drop in both the surface and total cellular receptor levels. Additional studies with the LDL receptor showed a similar effect. Surprisingly, immunofluorescence microscopy of imatinib-treated cells revealed a marked colocalization of internalized TfR1 with late endosomes/lysosomes, whereas attenuating the lysosome function with several inhibitors reduced this receptor loss. Importantly, inhibition of c-Abl resulted in a striking redistribution of the chaperone Hsc70 from a diffuse cytosolic localization to an association with the TfR1 at the late endosome-lysosome. Pharmacological inhibition of Hsc70 ATPase activity in cultured cells by the drug VER155008 prevents this chaperone-receptor interaction, resulting in an accumulation of the TfR1 in the early endosome. Thus, inhibition of c-Abl minimizes receptor recycling pathways and results in chaperone-dependent trafficking of the TfR1 to the lysosome for degradation. These findings implicate a novel role for c-Abl and Hsc70 as an unexpected regulator of Hsc70-mediated transport of trophic receptor cargo between the early and late endosomal compartments.

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“…MARCH1, an E3 ubiquitin ligase for MHCII and CD86, is incorporated into exosomes dependent on its C-t tyrosin-based motifs [81]. This endosome sorting motif is also important for sorting of transferrin receptor into exosomes due to its interaction with ALIX [82]. Nevertheless, whether MARCH1 is ubiquitinated or not in exosomes remains unclear, although this region is important for MARCH1 auto-ubiquitination [83].…”

Section: Ubiquitinated Proteins In Evsmentioning

confidence: 99%