Receptor-mediated Endocytosis 8 Utilizes an N-terminal Phosphoinositide-binding Motif to Regulate Endosomal Clathrin Dynamics

Xhabija, Besa; Vacratsis, Panayiotis O.

doi:10.1074/jbc.m115.644757

Cited by 21 publications

(32 citation statements)

References 53 publications

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“…2) [70]. Similar to Auxilin and GAK, RME-8 confers specificity to the Hsc70 chaperone through its J-domain [70][71][72][73]. Rather than uncoating CCVs, RME-8 has been found to regulate clathrin dynamics on early endosomes [74,75] (Fig.…”

Section: Dnajc26 (Gak) As Risk Factor For Parkinson's Diseasementioning

confidence: 99%

“…RME-8 has been found to interact both with SNX1, a component of the SNX dimer, as well as FAM21, a protein from the WASH complex [74,81]. RME-8 is recruited to early endosomes through interaction with PI(3)P [71,82]. RME-8 does not appear to bind to clathrin directly, but loss of either RME-8 or Hsc70 results in an accumulation of clathrin at early endosomes [70,74,83].…”

Section: Dnajc26 (Gak) As Risk Factor For Parkinson's Diseasementioning

confidence: 99%

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DNAJC proteins and pathways to parkinsonism

et al. 2019

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The DNAJC protein family is a subclass of heat shock proteins that has attracted recent attention due to the identification of mutations that are linked with parkinsonism, a feature of Parkinson's disease and other neurological disorders. In this review, we discuss the current genetic and functional evidence of the association of these DNAJC proteins with disease and how mutations in these proteins may contribute to disease pathogenesis. Although DNAJC6 (Auxilin), DNAJC12, and DNAJC5 (CSPα) exhibit strong genetic association with disease, DNAJC26 (GAK), DNAJC13 (RME‐8), and DNAJC10 (Erdj5) require additional evidence to definitively link reported variants to parkinsonism. Remarkably, multiple DNAJC proteins (Auxilin, GAK, RME‐8, CSPα) functionally converge on pathways of synaptic trafficking and clathrin dynamics, highlighting an important role of those pathways in the pathogenesis of parkinsonism. Further research is required to define the mechanisms through which these mutations contribute to disease etiology.

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Section: Dnajc26 (Gak) As Risk Factor For Parkinson's Diseasementioning

confidence: 99%

Section: Dnajc26 (Gak) As Risk Factor For Parkinson's Diseasementioning

confidence: 99%

DNAJC proteins and pathways to parkinsonism

et al. 2019

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“…In contrast, there is an autosomal‐dominant mutation that causes PD in RME‐8, and this mutation affects the region between two IWN repeats in the protein. Auxilin and RME‐8 are both co‐chaperones that at a step following endocytosis and together with Hsc70 and are independently involved in synaptic vesicle and early endosome uncoating (Fig ; Chang et al , ; Girard et al , ; Eisenberg & Greene, ; Xhabija & Vacratsis, ). This is interesting, because Hsc70 is the same protein that is involved in chaperone‐mediated autophagy and in endosomal microautophagy.…”

Section: Synaptic Autophagymentioning

confidence: 99%

Parkinson's disease: convergence on synaptic homeostasis

2018

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Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment-specific manner at the synapse where these proteins regulate endocytosis and autophagy. While this field is only recently emerging, the work suggests that the loss of synaptic homeostasis may contribute to neurodegeneration and is a key player in Parkinson's disease.

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“…For example, J-domain protein auxilin is required to disassemble clathrin from nascent endocytic vesicles shortly after they are released from the plasma membrane (21,22). In C. elegans, Drosophila, and mammals, loss of RME-8 leads to accumulation of clathrin on internal membranes (16,17,23). In mammalian cells, RME-8 has also been found to associate with the WASH actin nucleation complex, and cells depleted of RME-8 accumulate Snx1 on membrane tubules decorated with Vps35 and Vps26 (16,17,24).…”

mentioning

confidence: 99%

SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes

Norris

Tammineni

Wang

et al. 2017

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

100

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After endocytosis, transmembrane cargo reaches endosomes, where it encounters complexes dedicated to opposing functions: recycling and degradation. Microdomains containing endosomal sorting complexes required for transport (ESCRT)-0 component Hrs [hepatocyte growth factor-regulated tyrosine kinase substrate (HGRS-1) in Caenorhabditis elegans] mediate cargo degradation, concentrating ubiquitinated cargo and organizing the activities of ESCRT. At the same time, retromer associated sorting nexin one (SNX-1) and its binding partner, J-domain protein RME-8, sort cargo away from degradation, promoting cargo recycling to the Golgi. Thus, we hypothesized that there could be important regulatory interactions between retromer and ESCRT that balance degradative and recycling functions. Taking advantage of the naturally large endosomes of the C. elegans coelomocyte, we visualized complementary ESCRT-0 and RME-8/SNX-1 microdomains in vivo and assayed the ability of retromer and ESCRT microdomains to regulate one another. We found in snx-1(0) and rme-8(ts) mutants increased endosomal coverage and intensity of HGRS-1-labeled microdomains, as well as increased total levels of HGRS-1 bound to membranes. These effects are specific to SNX-1 and RME-8, as loss of other retromer components SNX-3 and vacuolar protein sorting-associated protein 35 (VPS-35) did not affect HGRS-1 microdomains. Additionally, knockdown of hgrs-1 had little to no effect on SNX-1 and RME-8 microdomains, suggesting directionality to the interaction. Separation of the functionally distinct ESCRT-0 and SNX-1/RME-8 microdomains was also compromised in the absence of RME-8 and SNX-1, a phenomenon we observed to be conserved, as depletion of Snx1 and Snx2 in HeLa cells also led to greater overlap of Rme-8 and Hrs on endosomes.endosome | SNX-1 | RME-8 | Hrs | clathrin

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Receptor-mediated Endocytosis 8 Utilizes an N-terminal Phosphoinositide-binding Motif to Regulate Endosomal Clathrin Dynamics

Cited by 21 publications

References 53 publications

DNAJC proteins and pathways to parkinsonism

DNAJC proteins and pathways to parkinsonism

Parkinson's disease: convergence on synaptic homeostasis

SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes

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