Hsp70 chaperones TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation

Gu, Jinge; Wang, Chen; Hu, Rirong; Li, Yichen; Zhang, Shengnan; Sun, Yunpeng; Wang, Qiangqiang; Li, Dan; Fang, Yanshan; Liu, Cong

doi:10.1038/s41422-021-00526-5

Cited by 37 publications

(43 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 2D 1 H- 15 N HSQC spectra of 15 N-labeled FUS low complex domain (FUS-LC) and 15 N-labeled TDP43-LC showed that both proteins adopted an intrinsically disordered conformation with a narrow chemical shift dispersion in the 1 H dimension (backbone amide resonances within 7.8–8.8 ppm) (Fig. S7), which is consistent with the previous reports (Burke et al, 2015 ; Conicella et al, 2016 ; Liu et al, 2020 ; Gu et al, 2021a ). We then used unlabeled N protein to titrate 15 N-labeled FUS-LC.…”

Section: Resultssupporting

confidence: 90%

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

et al. 2022

Protein Cell

Self Cite

View full text Add to dashboard Cite

The nucleocapsid (N) protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation, which enables its incorporation into stress granules (SGs) of host cells. However, whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow, neither do we know its consequence. Here, we used SARS-CoV-2 to infect mammalian cells and observed the incorporation of N protein into SGs, which resulted in markedly impaired self-disassembly but stimulated cell cellular clearance of SGs. NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific transient interactions, which not only expedites the phase transition of these proteins to aberrant amyloid aggregation in vitro, but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells. In addition, we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells. Our work indicates that SARS-CoV-2 infection can impair the disassembly of host SGs and promote the aggregation of SG-related amyloid proteins, which may lead to an increased risk of neurodegeneration.

show abstract

Section: Resultssupporting

confidence: 90%

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

et al. 2022

Protein Cell

Self Cite

View full text Add to dashboard Cite

show abstract

“…A variety of chaperones widely exist in the cytoplasm and membrane-bound organelles such as nucleus, endoplasmic reticulum, and mitochondrion ( Alderson et al., 2016 ; Moran Luengo et al., 2019 ). Recent studies have found that different chaperones such as Hsp90, Hsp70, and Hsp40 are also involved in the formation and regulation of different membrane-less organelles (MLOs) such as stress granules (SGs) and nuclear bodies (NBs) ( Mateju et al., 2017 ; Jain et al., 2016 ; O'Meara et al., 2019 ; Gu et al., 2020 ; Yu et al., 2021 ; Gu et al., 2021 ; Pare et al., 2009 ; Frottin et al., 2019 ). For instance, it has been reported that Hsp70 is important to facilitate the generation and maintain the dynamics of the TDP-43 nuclear bodies ( Yu et al., 2021 ; Gu et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have found that different chaperones such as Hsp90, Hsp70, and Hsp40 are also involved in the formation and regulation of different membrane-less organelles (MLOs) such as stress granules (SGs) and nuclear bodies (NBs) ( Mateju et al., 2017 ; Jain et al., 2016 ; O'Meara et al., 2019 ; Gu et al., 2020 ; Yu et al., 2021 ; Gu et al., 2021 ; Pare et al., 2009 ; Frottin et al., 2019 ). For instance, it has been reported that Hsp70 is important to facilitate the generation and maintain the dynamics of the TDP-43 nuclear bodies ( Yu et al., 2021 ; Gu et al., 2021 ). Hsp90 and AAA + ATPase VCP/p97 are involved in SG disassembly and degradation ( Mediani et al., 2021 ; Wang et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Hsp70 exhibits a liquid-liquid phase separation ability and chaperones condensed FUS against amyloid aggregation

Wang

et al. 2022

iScience

Self Cite

View full text Add to dashboard Cite

“…Recent evidences suggest the extensive incorporation of proteostasis components into the dynamic assembly MLOs to spatiotemporally maintain their quality. Molecular chaperones are implicated in preventing the accumulation of misfolding proteins in condensates as well as aberrant phase transitions (Mateju et a., 2017; Gu et al 2020, 2021; Boczek et al 2021; Lu et al 2021; Yoo et al 2022), suggesting roles for PQC machinery in condensate quality maintenance.…”

Section: Resultsmentioning

confidence: 99%

Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Mukherjee

Panda

Kasturi

2021

Preprint

View full text Add to dashboard Cite

Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membrane less organelles (MLOs) are biological condensates formed through liquid liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta analysis with age related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan. Interestingly, they are aggregating more in long-lived mutant worms compared to the age matched wildtype worms. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNA metabolism RNP components. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant worms, the MLOs may attain protective states due to enhanced proteostasis components and altered metabolism that eventually make these worms more protected.

show abstract

Hsp70 chaperones TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation

Cited by 37 publications

References 13 publications

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

Hsp70 exhibits a liquid-liquid phase separation ability and chaperones condensed FUS against amyloid aggregation

Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Contact Info

Product

Resources

About