Identification of cis-acting determinants mediating the unconventional secretion of tau

Katsinelos, Taxiarchis; McEwan, William A.; Jahn, Thomas R.; Nickel, Walter

doi:10.1038/s41598-021-92433-3

Cited by 15 publications

(11 citation statements)

References 87 publications

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“…Others have previously proposed that tau exits the cell via membrane translocation. Several reports have described fibril release from cells by direct membrane translocation from the cytoplasm to the extracellular space, dependent on HSPGs, although the details of how intracellular tau could bind an extracellular glycoprotein are not clear (Katsinelos et al, 2021; Katsinelos et al, 2018; Merezhko et al, 2018). The general idea of protein translocation across membranes is not new, as cell penetrating peptides (CPPs) and some antimicrobial peptides directly translocate across the membrane to move inside the cell (Kauffman et al, 2015; Scocchi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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Neurodegenerative tauopathies, including Alzheimer’s disease and related disorders, are caused by intracellular aggregation of tau protein in ordered assemblies. Experimental evidence suggests that tau assemblies propagate pathology across brain networks. Tau seeds enter cells through endocytosis but must access the cytoplasm to serve as templates for their own replication. The mechanism by which this occurs is unknown. To study tau uptake, we began with a whole-genome CRISPR knockout screen, which indicated a requirement vacuolar H+ ATPase (v-ATPase) components. Treatment with Bafilomycin A1, an inhibitor of the v-ATPase, also reduced tau entry. We next tested direct modifiers of endolysosomal trafficking. Dominant-negative Rab5a expression uniquely decreased tau uptake, as did temporary cold temperature during tau exposure, consistent with a primary role of endocytosis in tau uptake. However, despite reducing tau uptake, these interventions all paradoxically increased intracellular seeding. Consequently, we generated giant plasma membrane vesicles (GPMVs), which cannot undergo endocytosis, and observed that tau fibrils and monomer translocated into the vesicles, in addition to TAT peptide, whereas transferrin and albumin did not. In every case, tau required binding to heparan sulfate proteoglycans (HSPGs) for cell uptake, seeding, or GPMV entry. These findings are most consistent with direct translocation of tau seeds across the lipid bilayer, a novel mechanism of entry into the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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“…This is in-line with a previous report suggesting that covalent disulphide-mediated dimerisation plays an important role in the tau secretion process [ 17 ]. Interestingly, while this paper was in review, a report was published showing that the two cysteine residues are a critical cis ‐element in unconventional secretion of tau [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Membrane interaction and disulphide-bridge formation in the unconventional secretion of Tau

et al. 2021

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Misfolded, pathological Tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer’s disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of Tau takes place via several different routes, including direct penetration through the plasma membrane. Here, we show that Tau secretion requires membrane interaction via disulphide bridge formation. Mutating residues that reduce Tau interaction with membranes or formation of disulphide bridges decrease both Tau secretion from cells, and penetration through artificial lipid membranes. Our results demonstrate that Tau is indeed able to penetrate protein-free membranes in a process independent of active cellular processes and that both membrane interaction and disulphide bridge formation are needed for this process. QUARK-based de novo modelling of the second and third microtubule-binding repeat domains, in which the two cysteine residues of 4R isoforms of Tau are located, supports the concept that this region of Tau could form transient amphipathic helices for membrane interaction.

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“…In addition to hyper-phosphorylation these changes, including its distribution among adjacent neurons, are relevant in AD pathology [ 63 , 64 ]. Results that induce not only secretion but also spreading of tau by navigation of exosomes, are active for tauopathies and other related neurodegenerative diseases [ 65 , 66 ].…”

Section: Role Of Ups In Diseasesmentioning

confidence: 99%

Unconventional protein secretion (UPS): role in important diseases

Meldolesi

2023

Mol Biomed

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Unconventional protein secretion (UPS) is the new secretion process discovered in liquid form over three decades ago. More recently, UPS has been shown to operate also in solid forms generated from four types of organelles: fractions of lysosomes and autophagy (APh) undergoing exocytosis; exosomes and ectosomes, with their extracellular vesicles (EVs). Recently many mechanisms and proteins of these solid forms have been shown to depend on UPS. An additional function of UPS is the regulation of diseases, often investigated separately from each other. In the present review, upon short presentation of UPS in healthy cells and organs, interest is focused on the mechanisms and development of diseases. The first reported are neurodegenerations, characterized by distinct properties. Additional diseases, including inflammasomes, inflammatory responses, glial effects and other diseases of various origin, are governed by proteins generated, directly or alternatively, by UPS. The diseases most intensely affected by UPS are various types of cancer, activated in most important processes: growth, proliferation and invasion, relapse, metastatic colonization, vascular leakiness, immunomodulation, chemoresistence. The therapy role of UPS diseases depends largely on exosomes. In addition to affecting neurodegenerative diseases, its special aim is the increased protection against cancer. Its immense relevance is due to intrinsic features, including low immunogenicity, biocompatibility, stability, and crossing of biological barriers. Exosomes, loaded with factors for pharmacological actions and target cell sensitivity, induce protection against various specific cancers. Further expansion of disease therapies is expected in the near future.

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Identification of cis-acting determinants mediating the unconventional secretion of tau

Cited by 15 publications

References 87 publications

Tau seeds translocate across the cell membrane to initiate aggregation

Tau seeds translocate across the cell membrane to initiate aggregation

Membrane interaction and disulphide-bridge formation in the unconventional secretion of Tau

Unconventional protein secretion (UPS): role in important diseases

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