Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation

Hayer, Arnold; Stoeber, Miriam; Ritz, Danilo; Engel, Sabrina; Meyer, Hemmo; Helenius, Ari

doi:10.1083/jcb.201003086

Cited by 268 publications

(334 citation statements)

References 44 publications

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“…An additional complexity is that, Caveolin-1 is found at the plasma membrane and also in other sub-cellular compartments, such as endoplasmic reticulum (ER), Golgi, endosomes, mitochondria and associated with the nucleus [20][21][22]. Thus, much of the existing confusion related to Caveolin-1 function that will be discussed, likely reflects the fact that it is often unclear which pool of Caveolin-1 is implicated in a specific event.…”

Section: Introduction Caveolinsmentioning

confidence: 99%

The Caveolin-1 Connection to Cell Death and Survival

Quest

Lobos-González²,

Núñez³

et al. 2013

Current Molecular Medicine

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Abstract:Caveolins are a family of membrane proteins required for the formation of small plasma membrane invaginations called caveolae that are implicated in cellular trafficking processes. In addition to this structural role, these scaffolding proteins modulate numerous intracellular signaling pathways; often via direct interaction with specific binding partners. Caveolin-1 is particularly well-studied in this respect and has been attributed a large variety of functions. Thus, Caveolin-1 also represents the best-characterized isoform of this family with respect to its participation in cancer. Rather strikingly, available evidence indicates that Caveolin-1 belongs to a select group of proteins that function, depending on the cellular settings, both as tumor suppressor and promoter of cellular traits commonly associated with enhanced malignant behavior, such as metastasis and multi-drug resistance. The mechanisms underlying such ambiguity in Caveolin-1 function constitute an area of great interest. Here, we will focus on discussing how Caveolin-1 modulates cell death and survival pathways and how this may contribute to a better understanding of the ambiguous role this protein plays in cancer.

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Section: Introduction Caveolinsmentioning

confidence: 99%

The Caveolin-1 Connection to Cell Death and Survival

Quest

Lobos-González²,

Núñez³

et al. 2013

Current Molecular Medicine

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“…We next analyzed the effect of each loss-of-function mutation on the trafficking of CAV-1, the C. elegans homolog of caveolin-1, which was shown to undergo clathrin-mediated endocytosis and ubiquitin-dependent transport to the lysosome for degradation (26,27). In the proximal oocytes of control animals, CAV-1 resides on Golgi-derived cortical granules, which fuse en masse with the plasma membrane following fertilization and ovulation.…”

Section: The Fei Adaptor Complex Regulates Protein Sorting In the Endmentioning

confidence: 99%

Regulation of ubiquitin-dependent cargo sorting by multiple endocytic adaptors at the plasma membrane

Mayers¹,

Wang²,

Pramanik³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Endocytic protein trafficking is directed by sorting signals on cargo molecules that are recognized by cytosolic adaptor proteins. However, the steps necessary to segregate the variety of cargoes during endocytosis remain poorly defined. Using Caenorhabditis elegans, we demonstrate that multiple plasma membrane endocytic adaptors function redundantly to regulate clathrin-mediated endocytosis and to recruit components of the endosomal sorting complex required for transport (ESCRT) machinery to the cell surface to direct the sorting of ubiquitin-modified substrates. Moreover, our data suggest that preassembly of cargoes with the ESCRT-0 complex at the plasma membrane enhances the efficiency of downstream sorting events in the endolysosomal system. In the absence of a heterooligomeric adaptor complex composed of FCHO, Eps15, and intersectin, ESCRT-0 accumulation at the cell surface is diminished, and the degradation of a ubiquitin-modified cargo slows significantly without affecting the rate of its clathrin-mediated internalization. Consistent with a role for the ESCRT machinery during cargo endocytosis, we further show that the ESCRT-0 complex accumulates at a subset of clathrin-coated pits on the surface of human cells. Our findings suggest a unique mechanism by which ubiquitin-modified cargoes are sequestered into the endolysosomal pathway.clathrin | multivesicular endosome

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“…26 However, while caveosomes have been shown to fuse with early endosomes, 27 it was suggested recently that neutral caveosomes do not exist. 28 Polyethylenimine polyplexes, for instance, regardless of whether they are taken up by clathrindependent endocytosis or caveolin mediated endocytosis, are exposed to the acidic environ ment of early endosomes during the first 4 hours following transfection 23 and show efficient transfection uptake by both clathrinindependent endocytosis and clathrindependent endocytosis. 29 Caveolinmediated endocytosis actually involves trafficking to early or late endosomes (pH about 6 vs 5, respectively) depending on the metabolic state of the cell, which underscores the complexity of this pathway.…”

Section: Introductionmentioning

confidence: 99%

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Perez¹,

Cosaka²,

Romero³

et al. 2011

IJN

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Background: Gene silencing using small interfering RNA (siRNA) is a promising new therapeutic approach for glioblastoma. The endocytic uptake and delivery of siRNA to intra cellular compartments could be enhanced by complexation with polyamidoamine dendrimers. In the present work, the uptake mechanisms and intracellular traffic of siRNA/generation 7 dendrimer complexes (siRNA dendriplexes) were screened in T98G glioblastoma and J774 macrophages. Methods: The effect of a set of chemical inhibitors of endocytosis on the uptake and silenc ing capacity of dendriplexes was determined by flow cytometry. Colocalization of fluorescent dendriplexes with endocytic markers and occurrence of intracellular dissociation were assessed by confocal laser scanning microscopy. Results: Uptake of siRNA dendriplexes by T98G cells was reduced by methylβcyclodextrin, and genistein, and cytochalasine D, silencing activity was reduced by genistein; dendriplexes colocalized with cholera toxin subunit B. Therefore, caveolindependent endocytosis was involved both in the uptake and silencing activity of siRNA dendriplexes. On the other hand, uptake of siRNA dendriplexes by J774 cells was reduced by methylβcyclodextrin, genistein, chlorpromazine, chloroquine, cytochalasine D, and nocodazole, the silencing activity was not affected by chlorpromazine, genistein or chloroquine, and dendriplexes colocalized with transferrin and cholera toxin subunit B. Thus, both clathrindependent and caveolindependent endocytosis mediated the uptake and silencing activity of the siRNA dendriplexes. SiRNA dendriplexes were internalized at higher rates by T98G but induced lower silencing than in J774 cells. SiRNA dendriplexes showed relatively slow dissociation kinetics, and their escape towards the cytosol was not mediated by acidification independently of the uptake pathway. Conclusion: The extent of cellular uptake of siRNA dendriplexes was inversely related to their silencing activity. The higher silencing activity of siRNA dendriplexes in J774 cells could be ascribed to the contribution of clathrindependent and caveolindependent endocytosis vs only caveolindependent endocytosis in T98G cells.

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Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation

Abstract: Identification of the pathway by which caveolin-1 is degraded when caveolae assembly is compromised suggests that “caveosomes” may be endosomal accumulations of the protein awaiting degradation.

Cited by 268 publications

References 44 publications

The Caveolin-1 Connection to Cell Death and Survival

The Caveolin-1 Connection to Cell Death and Survival

Regulation of ubiquitin-dependent cargo sorting by multiple endocytic adaptors at the plasma membrane

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

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