Aggregation-prone Regions in HYPK Help It to Form Sequestration Complex for Toxic Protein Aggregates

Ghosh, Debasish Kumar; Ranjan, Akash

doi:10.1016/j.jmb.2018.02.007

Cited by 18 publications

(35 citation statements)

References 53 publications

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“…While previous studies have showed that VCP can interact with Huntingtin aggregates [53,54], it is not clear which segment of VCP mediates this association. Our study shows that the N-terminal region in VCP enables this interaction.…”

Section: Discussionmentioning

confidence: 84%

“…VCP/p97 protein was previously known to associate with polyglutamine‐expanded (mutant) Huntingtin aggregates . In our previous study, we had also shown that VCP was an interacting partner of aggregation‐prone Huntingtin‐exon1 protein . Though this interaction was reported, the interaction‐mediating motifs/domains in VCP and Huntingtin‐exon1 were not known.…”

Section: Resultsmentioning

confidence: 92%

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The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin‐exon1 aggregates

Ghosh

Ranjan

2018

FEBS Letters

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Intracellular protein aggregation is characterized by accumulation of misfolded proteins. Chaperones, degradation machineries, and quality-control mechanisms counteract protein aggregation. In this study, we report that the ATPase valosin-containing protein (VCP/p97) acts as a functional disaggregase that disassembles Huntingtin-exon1 aggregates in vitro and in HeLa cells. The N-terminal part of VCP (Cdc48_N domain) interacts with the N-terminal 17-amino acid region of Huntingtin-exon1. We show that VCP has properties of a disaggregase, since it is capable of reducing preformed protein aggregates and displays increased ATPase activity in the presence of protein aggregates. However, VCP shows high divergence/disparity from other disaggregases. Taken together, our studies show the novel function of VCP/p97 as a disaggregase which detangles protein aggregates to probably channelize their degradation.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 92%

The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin‐exon1 aggregates

Ghosh

Ranjan

2018

FEBS Letters

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“…HYPK is an aggregate-sequestering protein ( 20 ). Our earlier study had shown that the aggregate-sequestering function of HYPK is linked to the facilitated degradation of the aggregation-prone proteins ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

“…HYPK is an aggregate-sequestering protein ( 20 ). It can sequester the aggregates of huntingtin exon1, α-synuclein-A53T and superoxide dismutase 1-G93A.…”

Section: Introductionmentioning

confidence: 99%

“…It can sequester the aggregates of huntingtin exon1, α-synuclein-A53T and superoxide dismutase 1-G93A. The annular oligomers of HYPK, termed as H-granule, are involved in sequestering the protein aggregates ( 20 ). The balance of structural convolution of HYPK oligomers arises due to complex intra- and inter-molecular interactions of the hydrophobic regions, low complexity region and disordered nanostructure of HYPK ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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HYPK scaffolds the Nedd8 and LC3 proteins to initiate formation of autophagosome around polyneddylated huntingtin exon1 aggregates

Ghosh

Ranjan

2019

Preprint

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Selective autophagy of protein aggregates is necessary for maintaining the cellular proteostasis. Several regulatory proteins play critical roles in this process. Here, we report that the huntingtin interacting protein K (HYPK) modulates the autophagic degradation of poly-neddylated huntingtin exon1 aggregates. HYPK functions as a scaffolding protein that binds to the Nedd8 and LC3 proteins. The C-terminal ubiquitin-associated (UBA) domain of HYPK binds to the Nedd8, whereas an N-terminal tyrosine-type (Y-type) LC3 interacting region (LIR) of HYPK binds to the LC3. Several conserved amino acids in the UBA domain of HYPK are necessary to mediate the efficient binding of HYPK to Nedd8. The autophagy inducing properties of HYPK are manifested by the increased lipidation of LC3 protein, increased expression of beclin-1 and ATG-5 proteins, and generation of puncta-like granules of LC3 in the HYPK overexpressing cells. Association of the ‘H-granules’ of HYPK with the poly-neddylated huntingtin exon1 aggregates results in the formation of autophagosome around the huntingtin exon1 aggregates, thereby clearing the aggregates by aggrephagy. Poly-neddylation of huntingtin exon1 is required for its autophagic degradation by HYPK. Thus, overexpression of Nedd8 also increases the basal level of cellular autophagy, other than maintaining the autophagy flux. The poly-neddylation dependent autophagic clearance of huntingtin exon1 by HYPK leads to better cell physiology and survival. Taken together, our study describes a novel mechanism of HYPK mediated autophagy of poly-neddylated huntingtin exon1 aggregates.

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Ubiquitin‐Modulated Phase Separation of Shuttle Proteins: Does Condensate Formation Promote Protein Degradation?

Dao

Castañeda

2020

BioEssays

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Liquid-liquid phase separation (LLPS) has recently emerged as a possible mechanism that enables ubiquitin-binding shuttle proteins to facilitate the degradation of ubiquitinated substrates via distinct protein quality control (PQC) pathways. Shuttle protein LLPS is modulated by multivalent interactions among their various domains as well as heterotypic interactions with polyubiquitin chains. Here, the properties of three different shuttle proteins (hHR23B, p62, and UBQLN2) are closely examined, unifying principles for the molecular determinants of their LLPS are identified, and how LLPS is connected to their functions is discussed. Evidence supporting LLPS of other shuttle proteins is also found. In this review, it is proposed that shuttle protein LLPS leads to spatiotemporal regulation of PQC activities by mediating the recruitment of PQC machinery (including proteasomes or autophagic components) to biomolecular condensates, assembly/disassembly of condensates, selective enrichment of client proteins, and extraction of ubiquitinated proteins from condensates in cells.

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Aggregation-prone Regions in HYPK Help It to Form Sequestration Complex for Toxic Protein Aggregates

Cited by 18 publications

References 53 publications

The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin‐exon1 aggregates

The ATPase VCP/p97 functions as a disaggregase against toxic Huntingtin‐exon1 aggregates

HYPK scaffolds the Nedd8 and LC3 proteins to initiate formation of autophagosome around polyneddylated huntingtin exon1 aggregates

Ubiquitin‐Modulated Phase Separation of Shuttle Proteins: Does Condensate Formation Promote Protein Degradation?

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