ESCRTs and associated proteins in lysosomal fusion with endosomes and autophagosomes

Majumder, Priyanka; Chakrabarti, Oishee

doi:10.1139/bcb-2016-0099

Cited by 3 publications

(1 citation statement)

References 90 publications

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“…The endosome-lysosome pathway is an important protein clearance mechanism that directs the engulfment of protein cargo and trafficking to the lysosome for degradation. A key to this process is the endosomal sorting complex required for transport (ESCRT) machinery, which mediates multivesicular body (MVB) formation and fusion with the lysosome [55]. Additionally, deficits in ESCRT and the endosome-lysosome pathway have been observed in AD and other neurodegenerative diseases [32].…”

Section: Introductionmentioning

confidence: 99%

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lin

Tang

et al. 2021

Preprint

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The decline in proteostasis during aging is a major contributing factor to increased susceptibility to neurodegenerative diseases such as Alzheimer’s disease. Although dysfunction of the autophagy pathway is likely one of the contributors, emerging studies implicate that impairment of the endosome-lysosome pathway is also a significant factor in the pathogenesis of these diseases. Our lab was the first to demonstrate that BAG3 facilitates phosphorylated tau clearance through autophagy. However, we did not fully define the mechanisms by which BAG3 regulates endogenous tau proteostasis. Here, we applied mass spectrometric analyses and found a major group of neuronal BAG3 interactors are in the endocytic pathway. Among them were key regulators of small GTPases. Excitingly one of these was the Rab35 GTPase activating protein, TBC1D10B. Our data demonstrate that a BAG3-HSP70-TBC1D10B complex attenuates the ability of TBC1D10B to inactivate Rab35. Thus BAG3, through its interaction with TBC1D10B supports the activation of Rab35 and recruitment of Hrs, which initiates ESCRT-mediated endosomal tau clearance. Further, intrahippocampal expression of BAG3 in P301S mice increased the co-localization of phospho-tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau. Overall, our data provide evidence of a novel BAG3-TBC1D10B-Rab35 regulatory axis in modulating vacuolar dependent protein degradation machinery through ESCRT. These findings expand our understanding of the role of BAG3 in neuronal proteostasis, and how dysregulation could contribute to the pathogenesis of Alzheimer’s disease, as well as other neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lin

Tang

et al. 2021

Preprint

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Lysosomal Quality Control in Prion Diseases

Majumder

Chakrabarti

2017

Mol Neurobiol

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Prion diseases are transmissible, familial or sporadic. The prion protein (PrP), a normal cell surface glycoprotein, is ubiquitously expressed throughout the body. While loss of function of PrP does not elicit apparent phenotypes, generation of misfolded forms of the protein or its aberrant metabolic isoforms has been implicated in a number of neurodegenerative disorders such as scrapie, kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker and bovine spongiform encephalopathy. These diseases are all phenotypically characterised by spongiform vacuolation of the adult brain, hence collectively termed as late-onset spongiform neurodegeneration. Misfolded form of PrP (PrP) and one of its abnormal metabolic isoforms (the transmembrane PrP) are known to be disease-causing agents that lead to progressive loss of structure or function of neurons culminating in neuronal death. The aberrant forms of PrP utilise and manipulate the various intracellular quality control mechanisms during pathogenesis of these diseases. Amongst these, the lysosomal quality control machinery emerges as one of the primary targets exploited by the disease-causing isoforms of PrP. The autophagosomal-lysosomal degradation pathway is adversely affected in multiple ways in prion diseases and may hence be regarded as an important modulator of neurodegeneration. Some of the ESCRT pathway proteins have also been shown to be involved in the manifestation of disease phenotype. This review discusses the significance of the lysosomal quality control pathway in affecting transmissible and familial types of prion diseases.

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BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance

Lin

Tang

et al. 2022

Biological Psychiatry

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ESCRTs and associated proteins in lysosomal fusion with endosomes and autophagosomes

Cited by 3 publications

References 90 publications

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lysosomal Quality Control in Prion Diseases

BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance

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