Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3

Zeng, Li; Wang, Bo; Merillat, Sean; Minakawa, Eiko N.; Perkins, Matthew; Ramani, Biswarathan; Tallaksen-Greene, Sara J.; Costa, Maria do Carmo; Albin, Roger L.; Paulson, Henry L.

doi:10.1016/j.nbd.2015.06.017

Cited by 24 publications

(25 citation statements)

References 39 publications

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“…Htt-NTFs consist of a 17-residue N-terminal stretch (MATLEKLMKAFESLKSF) designated as N17, a polyQ tract of length n (Q n ), and a 38-residue C-terminal stretch (C38) that includes two polyproline (polyP) modules P 11 and P 10 connected by a 17-residue linker denoted as L17 (QLPQPPPQAQPLLPQPQ) (Figure 1a). In transgenic mouse models, Htt-NTFs produce robust degeneration of the relevant neurons (35).Although HD is characterized by Htt-NTF inclusions, the role of these inclusions as agents of neurotoxicity has been the topic of considerable debate (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). In a recent study, Ramzdan et al showed that both soluble species and insoluble deposits engender neurotoxicity, albeit through very different mechanisms (45).…”

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confidence: 99%

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Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

122

117

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Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We find that monomers and oligomers make up the soluble M-phase, ~25 nm spheres dominate in the soluble S-phase, and long, linear fibrils make up the insoluble F-phase. Previous studies showed that profilin, an abundant cellular protein, reduces Htt-NTF aggregation and toxicity in cells. We confirm that profilin achieves its cellular effects through direct binding to the C-terminal proline-rich region of Htt-NTFs. We show that profilin preferentially binds to Htt-NTF M-phase species and destabilizes aggregation and phase separation by shifting the concentration boundaries for phase separation to higher values through a process known as polyphasic linkage. Our experiments, aided by coarse-grained computer simulations and theoretical analysis, suggest that preferential binding of profilin to the Mphase species of Htt-NTFs is enhanced through a combination of specific interactions between profilin and polyproline segments and auxiliary interactions between profilin and polyglutamine tracts. Polyphasic linkage may be a general strategy that cells utilize to regulate phase behavior of aggregation-prone proteins. Accordingly, detailed knowledge of phase behavior and an understanding of how ligands modulate phase boundaries may pave the way for developing new therapeutics against a variety of aggregation-prone proteins.Many diseases are associated with protein misfolding and aggregation (1,2). The aggregation process is often characterized by the presence of one or more threshold concentrations at which a sharp, discontinuous change to some aspect of the assembly state (e.g., size, conformational characteristics, material properties) occurs (3-6). Such a change can be described using the concepts of phase transitions. Phase separation, a subcategory of phase transitions, has recently received considerable attention due to increasing recognition of its importance in cell biology (7)(8)(9)(10)(11)(12)(13). Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25) Modulation of Htt-NTF aggregation via polyphasic linkage2 separation are quantified in terms of saturation concentrations (14,19,26). For a given two-phase system, the saturation concentration is the bulk concentration of the protein beyond which the solution separates into two coexisting phases. The lower the saturation concentration, t...

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confidence: 99%

“…Although HD is characterized by Htt-NTF inclusions, the role of these inclusions as agents of neurotoxicity has been the topic of considerable debate (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). In a recent study, Ramzdan et al showed that both soluble species and insoluble deposits engender neurotoxicity, albeit through very different mechanisms (45).…”

mentioning

confidence: 99%

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

122

117

View full text Add to dashboard Cite

show abstract

“…Besides the disease‐related proteins, the protein inclusions also contain various other cellular partners, including components of the ubiquitin (Ub)‐proteasome system (UPS) (5–10), autophagy receptors (11–13), molecular chaperones (14–16), and transcription factors (17–19). For different pathogenic proteins, some components colocalized within the inclusions are unique, whereas some are identical, such as Ub and Ub chains (6, 9, 20–22), proteasome components (5, 7, 8, 10), sequestosome‐1/P62 (11), human RAD23 homolog B (hHR23B) (23, 24), ubiquilin (UBQLN)‐2 (25), valosin‐containing protein (VCP)/P97 (26, 27), and so on. Then, why the inclusions formed by different ND‐pathogenic proteins commonly contain Ub or Ub‐related proteins remains to be elucidated.…”

mentioning

confidence: 99%

“…Recently, accumulating evidence has demonstrated that sequestration of cellular interacting partners by protein aggregates or inclusions is a common source of cytotoxicity and neurodegeneration of NDs (16, 23, 25–30). Based on recent research, it is likely that specific molecular interaction is the prerequisite for sequestration by protein aggregates (28, 31, 32).…”

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confidence: 99%

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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“…Mutations in Atx3 and P62, which disrupt their interactions with Ub, abolish their recruitments into the polyQ aggregates , implying that other normal Ub‐binding proteins are also sequestered in the same way. Interestingly, recent research showed that ubiquilin‐2, a proteasome adaptor with Ub‐binding ability, is selectively sequestered into the inclusions in HD, but not in spinocerebellar ataxia 3 (SCA3), due to its interaction with mutant Htt via the UBA domain , implying that the components of UPS may be differentially sequestered into inclusions in different types of NDs.…”

Section: Specific Interaction Is Important For Sequestrationmentioning

confidence: 99%

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

2016

The FEBS Journal

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Protein misfolding and aggregation are a hallmark of several neurodegenerative diseases (NDs). However, how protein aggregation leads to cytotoxicity and neurodegeneration is still controversial. Emerging evidence demonstrates that sequestration of cellular-interacting partners by protein aggregates contributes to the pathogenesis of these diseases. Here, we review current research on sequestration of cellular proteins by protein aggregates and its relation to proteinopathies. Based on different interaction modes, we classify these protein sequestrations into four types: protein coaggregation, domain/motif-mediated sequestration, RNA-assisted sequestration, and sequestration of molecular chaperones. Thus, the cellular essential proteins and/or RNA hijacked by protein aggregates may lose their biological functions, consequently resulting in cytotoxicity and neurodegeneration. We have proposed a hijacking model recapitulating the sequestration process and the loss-of-function pathology of ND.

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Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3

Cited by 24 publications

References 39 publications

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

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

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

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