Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation

Liu, Zhenying; Zhang, Shengnan; Gu, Jinge; Tong, Yilun; Li, Yichen; Gui, Xingmin; Long, Houfang; Wang, Chuchu; Zhao, Chunyu; Lu, Jianping; He, Lin; Liu, Ying; Liu, Zhijun; Li, Dan; Liu, Cong

doi:10.1038/s41594-020-0399-3

Cited by 134 publications

(127 citation statements)

References 55 publications

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“…Moreover, BAG3 is recruited to stress granules via its interactions with HSPB8 where the BAG3‐HSPB8‐HSP70 complex plays a key role in ensuring stress granule functionality (Ganassi et al, 2016). Likewise, it has been shown that HSP27 is also recruited to stress granules (Ganassi et al, 2016; Jain et al, 2016) and that it plays a direct role in chaperoning proteins inside stress granules (Liu et al, 2020). Therefore, disturbing the dynamic balance of the HSP27‐BAG3 interaction might therefore affect a wider chaperone network and contribute to destabilization of proteostasis (Meriin et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulated binding of the NTD to the β4/β8 groove could have implications for the chaperone mechanism of HSP27, as recent NMR data have indicated that aggregation-prone substrates can either bind to the NTD, the ACD, or the β4/β8 groove (Mainz et al, 2015;Freilich et al, 2018;Baughman et al, 2020;Liu et al, 2018Liu et al, , 2020, and HSP27-substrate interactions involving the β4/β8 groove may not always prevent substrate aggregation (Baughman et al, 2020). For such substrates that interact with the β4/β8 groove, the binding affinities appear to be very weak (Baughman et al, 2018;Freilich et al, 2018;Liu et al, 2018Liu et al, , 2020, and these interactions would exist in competition with binding of the IxI/V motif. Therefore, increased availability of the β4/β8 groove in P182L IxI/V would leave its β4/β8 groove more accessible to interactions with other inter-and intramolecular contacts and could reduce the number of NTDsubstrate interactions and decrease the overall chaperone activity of the HSP27 chaperone.…”

Section: Of 23mentioning

confidence: 99%

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A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

et al. 2021

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HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot‐Marie‐Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C‐terminal region, which interacts weakly with the structured core domain of HSP27. Here, we observed that the P182L mutation disrupts the chaperone activity and significantly increases the size of HSP27 oligomers formed in vivo, including in motor neurons differentiated from CMT patient‐derived stem cells. Using NMR spectroscopy, we determined that the P182L mutation decreases the affinity of the HSP27 IxI/V motif for its own core domain, leaving this binding site more accessible for other IxI/V‐containing proteins. We identified multiple IxI/V‐bearing proteins that bind with higher affinity to the P182L variant due to the increased availability of the IxI/V‐binding site. Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27 and suggest that the IxI/V motif plays an important, regulatory role in modulating protein–protein interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Of 23mentioning

confidence: 99%

A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

et al. 2021

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“…Furthermore, Sgta, Hspb1 and Snu13 appeared to develop a greater enrichment to the outer shell of the mature inclusions, suggesting they are continuously enriched as inclusions mature. Previously it was shown that Hspb1 can form molecular condensates, which raises the possibility of a mixed phase separation process with polyQ that may explain some of the co-aggregation mechanism [ 36 , 37 ]. Phase separation could also involve multiple immiscible phases embedded inside one another [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Nascent mutant Huntingtin exon 1 chains do not stall on ribosomes during translation but aggregates do recruit machinery involved in ribosome quality control and RNA

et al. 2020

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Mutations that cause Huntington’s Disease involve a polyglutamine (polyQ) sequence expansion beyond 35 repeats in exon 1 of Huntingtin. Intracellular inclusion bodies of mutant Huntingtin protein are a key feature of Huntington’s disease brain pathology. We previously showed that in cell culture the formation of inclusions involved the assembly of disordered structures of mHtt exon 1 fragments (Httex1) and they were enriched with translational machinery when first formed. We hypothesized that nascent mutant Httex1 chains co-aggregate during translation by phase separation into liquid-like disordered aggregates and then convert to more rigid, amyloid structures. Here we further examined the mechanisms of inclusion assembly in a human epithelial kidney (AD293) cell culture model. We found mHttex1 did not appear to stall translation of its own nascent chain, or at best was marginal. We also found the inclusions appeared to recruit low levels of RNA but there was no difference in enrichment between early formed and mature inclusions. Proteins involved in translation or ribosome quality control were co-recruited to the inclusions (Ltn1 Rack1) compared to a protein not anticipated to be involved (NACAD), but there was no major specificity of enrichment in the early formed inclusions compared to mature inclusions. Furthermore, we observed co-aggregation with other proteins previously identified in inclusions, including Upf1 and chaperone-like proteins Sgta and Hspb1, which also suppressed aggregation at high co-expression levels. The newly formed inclusions also contained immobile mHttex1 molecules which points to the disordered aggregates being mechanically rigid prior to amyloid formation. Collectively our findings show little evidence that inclusion assembly arises by a discrete clustering of stalled nascent chains and associated quality control machinery. Instead, the machinery appear to be recruited continuously, or secondarily, to the nucleation of inclusion formation.

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“…Specificity for the protein-driven LLPS can be achieved by proteins having repetitive modular domains and intrinsically disordered regions with weakly adhesive motifs. Post-translational modifications of RBPs (including poly-ADP-ribosylation, e.g., [61]), phosphorylation (e.g., [62]), and arginine methylation (e.g., [63]) or their protein partners (e.g., [64]) emerged as important regulators of LLPS. Intermolecular interactions between RNAs, promoted by high local RNA concentrations and driven by specific sequences and structures (canonical or non-canonical), are believed to trigger RNA condensation necessary for RNP formation.…”

Section: Rg4s and Phase Transitionsmentioning

confidence: 99%

G-Quadruplexes in RNA Biology: Recent Advances and Future Directions

Dumas

Herviou

Dassi

et al. 2021

Trends in Biochemical Sciences

133

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Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation

Cited by 134 publications

References 55 publications

A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

Nascent mutant Huntingtin exon 1 chains do not stall on ribosomes during translation but aggregates do recruit machinery involved in ribosome quality control and RNA

G-Quadruplexes in RNA Biology: Recent Advances and Future Directions

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