Sequestration of cellular interacting partners by protein aggregates: implication in a loss‐of‐function pathology

Ye, Hui; Hu, Hongyu

doi:10.1111/febs.13722

Cited by 80 publications

(58 citation statements)

References 159 publications

(233 reference statements)

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“…However, the absence of significant neuronal abnormalities in tau knock-out mice 9 have suggested that the loss of tau function may be less critical and the gain of toxic function in the process of tau aggregate formation might be the key factor in neurodegeneration. Several recent evidences also suggest that sequestration of cellular interacting partners (proteins or RNA) by protein aggregates could contribute to pathogenesis in a wide spectrum of neurodegenerative diseases 10 . The fact, that the intrinsically unstructured tau protein is capable of interacting with polyanionic cofactors like heparin 11 and cellular RNAs 12 , raises the possibility that the tau protein is also capable of interacting with highly charged macromolecular complexes such as the ribosome.…”

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confidence: 99%

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

Banerjee

Ferdosh

Ghosh

et al. 2020

Sci Rep

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the human tau is a microtubule-associated intrinsically unstructured protein that forms intraneuronal cytotoxic deposits in neurodegenerative diseases, like tauopathies. Recent studies indicate that in Alzheimer's disease, ribosomal dysfunction might be a crucial event in the disease pathology. our earlier studies had demonstrated that amorphous protein aggregation in the presence of ribosome can lead to sequestration of the ribosomal components. The present study aims at determining the effect of incubation of the full-length tau protein (Ht40) and its microtubule binding 4-repeat domain (K18) on the eukaryotic ribosome. our in vitro studies show that incubation of Ht40 and the K18 tau variants with isolated non-translating yeast ribosome can induce a loss of ribosome physical integrity resulting in formation of tau-rRnA-ribosomal protein aggregates. incubation with the tau protein variants also led to a disappearance of the peak indicating the ribosome profile of the HeLa cell lysate and suppression of translation in the human in vitro translation system. the incubation of tau protein with the ribosomal RNA leads to the formation of tau-rRNA aggregates. The effect of K18 on the yeast ribosome can be mitigated in the presence of cellular polyanions like heparin and tRnA, thereby indicating the electrostatic nature of the aggregation process.

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confidence: 99%

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

Banerjee

Ferdosh

Ghosh

et al. 2020

Sci Rep

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“…Our laboratory proposed that protein aggregates sequester cellular interacting partners, resulting in cytotoxicity or neurodegeneration (33). To define whether polyQ‐expanded proteins sequester Ub adaptors into protein aggregates, we applied polyQ‐expanded Htt‐N552 (residues 1–552) and Atx‐3 (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The hijacking model implies that sequestration of cellular interacting partners by protein aggregates deteriorates the normal function of the hijacked partners, not only by phase transition or mislocalization but also by reducing their available quantities (27, 33). As hHR23B is able to stabilize the xeroderma pigmentosum group C (XPC) protein functioning in DNA repair (41, 54, 55), we investigated the effect of polyQ‐expanded proteins on the XPC level.…”

Section: Resultsmentioning

confidence: 99%

“…Based on recent research, it is likely that specific molecular interaction is the prerequisite for sequestration by protein aggregates (28, 31, 32). We have proposed a hijacking model for the sequestration processes on the cytotoxicity and neurodegeneration caused by protein aggregates (27, 33), and classified the protein sequestration into 4 types according to their interaction modes: protein coaggregation, domain/motif‐mediated sequestration, RNA‐assisted sequestration, and sequestration of molecular chaperones (33). Among these, domain/motif–mediated sequestration is a kind of sequestration through specific interactions mediated by domains or motifs of the related proteins.…”

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confidence: 99%

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PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin

Yue

et al. 2018

FASEB j.

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The components of ubiquitin (Ub)-proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub-related proteins remains elusive. Using N-terminal huntingtin (Htt-N552) and ataxin (Atx)-3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ-expanded proteins. We found that polyQ-expanded Htt-N552 and Atx-3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)-2, into inclusions. This sequestration effect is dependent on the UBA domains of Ub adaptors and the conjugated Ub of the aggregated proteins. Moreover, polyQ-expanded Htt-N552 and Atx-3 reduce the protein level of xeroderma pigmentosum group C (XPC) by sequestration of hHR23B, suggesting that this process may cut down the available quantity of hHR23B and thus affect its normal function in stabilizing XPC. Our findings demonstrate that polyQ-expanded proteins sequester Ub adaptors or other Ub-related proteins into aggregates or inclusions through ubiquitination of the pathogenic proteins. This study may also provide a common mechanism for the formation of Ub-positive inclusions in cells.-Yang, H., Yue, H.-W., He, W.-T., Hong, J.-Y., Jiang, L.-L., Hu, H.-Y. PolyQ-expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin.

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“…Brain proteins like neurofilaments (Nf) can leak from aggregates-containing neurons and axons undergoing degeneration into extra-cellular fluid, making their way into cerebrospinal fluid (CSF) and blood. In biofluids, proteins like Nf may transiently assemble into circulating protein aggregates (CPA), similarly to what is described for stress granule-like formations in tissues such as brain ( 7 ). Using ultracentrifugation (UC) and low-complexity binders to extract CPA from plasma of healthy individuals, we have recently shown that CPA are enriched with heavy chain neurofilament (NfH) and not with the light and medium isoforms (NfL, NfM).…”

Section: Introductionmentioning

confidence: 79%

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

Adiutori

Puentes

Bremang

et al. 2020

Preprint

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Blood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.Significance StatementMolecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.

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Sequestration of cellular interacting partners by protein aggregates: implication in a loss‐of‐function pathology

Cited by 80 publications

References 159 publications

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

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