The role of ubiquitylation in receptor endocytosis and endosomal sorting

Haglund, Kaisa; Đikić, Ivan

doi:10.1242/jcs.091280

Cited by 283 publications

(261 citation statements)

References 182 publications

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“…To corroborate that morphological and biochemical alterations were accompanied by dysfunction, we monitored p62 levels and the rate of degradation of the EGF receptor (EGFR), which, on binding of its ligand EGF, is ubiquitinated and sorted for lysosomal degradation. 26 Consistent with deficient autophagy, p62 levels were increased in the NPA fibroblasts (Figure 4e). In agreement with defective lysosomal degradation, the amount of EGFR at 30, 60 and 120 min after EGF stimulation decreased by 15%, 45% and 30%, respectively, in control fibroblasts, whereas in NPA fibroblasts EGFR levels increased 185 and 115% at 30 and 60 min and diminished (by a 27%) only at the latest time monitored after stimulation (120 min) (Figure 4f).…”

Section: Resultsmentioning

confidence: 64%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

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Section: Resultsmentioning

confidence: 64%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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“…In addition, several other proteins that are structurally related to ESCRT-0 have been proposed to work in parallel to ESCRT-0 as alternative early Ub-cargo receptors. These include Tom1, Tom1L1, and GGA3, which bind clathrin, Ub, and ESCRT-I supporting the idea that several ESCRT-0-like complexes gather Ub cargo and pass it to a central ESCRT-I/-II supercomplex (Shields and Piper 2011;Haglund and Dikic 2012). Recently, other contenders for Ub-sorting receptors have been identified including Bro1, Alix, and HD-PTP, which bind Ub, and interact with ESCRT-I and ESCRT-III (Ali et al 2013;Pashkova et al 2013).…”

Section: Sequential Orchestration Of Escrt Functionmentioning

confidence: 85%

“…Often, UBDs confer ubiquitination owing to the fact that proteins with UBDs can bind Ub chains that bring them into the proximity of Ub ligases forming those chains. A potential role for ubiquitination of the machinery is that it could mediate interaction with UBDs in either intra-or intermolecular interactions (Haglund and Dikic 2012). Artificial ubiquitination of ESCRTs can inactivate them.…”

Section: Roles Of Multiple Ubdsmentioning

confidence: 99%

“…This facilitates multiple-mono-and Lys63-linked polyubiquitination in a manner dependent on the Ubc4-and Ubc5-conjugating enzymes (Haglund et al 2003;Huang et al 2006Huang et al , 2007. Other RTKs, such as those for hepatocyte growth factor (HGF), vascular endothelial growth factor receptor (VEGFR-1), and platelet-derived growth factor (PDGF) receptors, also rapidly undergo ligand-stimulated ubiquitination by Cbl (Haglund and Dikic 2012). Cbl has other targets as well, such as integrins, which connect cells to the extracellular matrix to control cell adhesion, migration, and proliferation.…”

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confidence: 99%

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Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

194

176

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When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

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“…Ubiquitin serves as a post-translational modifier and is involved in the regulation of a vast array of cellular processes such as cell cycle, endocytosis, and DNA repair [2][3][4]. Ubiquitin signals are generated through covalent attachment of ubiquitin molecules to the target proteins in a process known as ubiquitylation.…”

Section: Introductionmentioning

confidence: 99%

Selectivity of the ubiquitin‐binding modules

Rahighi

Đikić

2012

FEBS Letters

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a b s t r a c tUbiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin-binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling via the NF-jB pathway, and autophagy.

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The role of ubiquitylation in receptor endocytosis and endosomal sorting

Cited by 283 publications

References 182 publications

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Ubiquitin-Dependent Sorting in Endocytosis

Selectivity of the ubiquitin‐binding modules

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