The Hsp70 chaperone network

Rosenzweig, Rina; Nillegoda, Nadinath B.; Mayer, Mathias; Bukau, Bernd

doi:10.1038/s41580-019-0133-3

Cited by 798 publications

(900 citation statements)

References 167 publications

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“…4F-H) that the annular shell rapidly merged with the liquid core when the HSP70 affinity for TDP-43 was elevated by mild temperature increase (49) or by transiently locking the chaperones onto their clients by inhibition of their ATPase cycles ( Fig. 6D) (45).…”

Section: Discussionmentioning

confidence: 99%

“…Each HSP70 family member requires ATP hydrolysis to fulfill its protein folding chaperone function (45). After addition of an HSP70 inhibitor thought to block ATP hydrolysis by all family members (46) and to lock chaperone binding to a client protein (45), live imaging revealed that inhibition of HSP70 chaperone activity induced TDP-43 2KQ -containing annuli conversion (within 10 minutes) into small droplets of uniformly distributed TDP-43 2KQ and HSP70, which then fused within an additional 30~60 minutes into a single large granule (Figs. 6D, S10D,E).…”

Section: Hsp70 Chaperones Drive Ilsa By Forming the Inner Liquid Corementioning

confidence: 99%

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TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

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One Sentence Summary:Acetylation of TDP-43 drives its phase separation into spherical annuli that form a liquid-insidea-liquid-inside-a-liquid. AbstractThe RNA binding protein TDP-43 naturally phase separates within cell nuclei and forms cytoplasmic aggregates in age-related neurodegenerative diseases. Here we show that acetylation-mediated inhibition of TDP-43 binding to RNA produces co-de-mixing of acetylated and unmodified TDP-43 into symmetrical, intranuclear spherical annuli whose shells and cores have liquid properties. Shells are anisotropic, like liquid crystals. Consistent with our modelling predictions that annulus formation is driven by components with strong self-interactions but weak interaction with TDP-43, the major components of annuli cores are identified to be HSP70 family proteins, whose chaperone activity is required to maintain liquidity of the core. Proteasome inhibition, mimicking reduction in proteasome activity during aging, induces TDP-43-containing annuli in neurons in rodents. Thus, we identify that TDP-43 phase separation is regulated by acetylation, proteolysis, and ATPase-dependent chaperone activity of HSP70.A seminal discovery in the last decade has been recognition that large biological molecules, especially RNA binding proteins, can undergo liquid-liquid phase separation (LLPS), resembling oil droplets in vinegar. Under certain physical conditions, proteins, nucleic acids, or a mixture of both in a complex solution can form two phases, a condensed de-mixed phase and more dilute aqueous phase (1). Inside the cell, proteins and/or nucleic acids de-mix into a condensed phase to form membraneless organelles which have been proposed to promote biological functions (2).One membraneless organelle is the nucleolus, first described in the early 1800's and now recognized to be composed of proteins that undergo LLPS (3-5). Discovery that P-granules are de-mixed compartments with liquid behaviour brought widespread recognition to LLPS and its ability to mediate subcellular compartmentalization in a biological context (6). Phase separation has been also proposed for heterochromatin and RNA bodies (1, 6, 7). LLPS potentially underlies the operational principle governing formation of important organelles and structures, such as centrosomes, nuclear pore complexes, and super enhancers (8-10).Few mechanisms to modulate intracellular LLPS have been identified. Disease-causing mutations of proteins such as FUS (11) and HNRNPA2B1 (12) alter their LLPS behaviors in vitro, but the physiological or pathological relevance of their intracellular LLPS has not been fully elucidated. Random, multivalent interactions among intrinsically disordered, low complexity domains (LCDs) of proteins are a major driving force for LLPS in vitro. Oligomerization of other domains is thought to be required for LLPS in vivo (13). The inherent randomness of multivalent interactions (14) favors a model of disordered alignment -a conventional liquid phase in which molecules randomly move. The evidence is compelling that multi...

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Section: Discussionmentioning

confidence: 99%

Section: Hsp70 Chaperones Drive Ilsa By Forming the Inner Liquid Corementioning

confidence: 99%

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

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“…In fact, HSP70 refers to a family of 70 kDa chaperone proteins participating in house-keeping functions. These ATP-dependent chaperones are key elements of the cellular protein surveillance network involved in a large variety of protein-folding processes [128]. It is well appreciated that under various stress conditions, adaptive synthesis of stress inducible HSP70 enhances the ability of stressed cells to maintain proteostasis by dealing with increased concentrations of unfolded or denatured proteins (for recent reviews, see References [129][130][131][132]).…”

Section: Hsp70mentioning

confidence: 99%

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

et al. 2019

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Poultry in commercial settings are exposed to a range of stressors. A growing body of information clearly indicates that excess ROS/RNS production and oxidative stress are major detrimental consequences of the most common commercial stressors in poultry production. During evolution, antioxidant defence systems were developed in poultry to survive in an oxygenated atmosphere. They include a complex network of internally synthesised (e.g., antioxidant enzymes, (glutathione) GSH, (coenzyme Q) CoQ) and externally supplied (vitamin E, carotenoids, etc.) antioxidants. In fact, all antioxidants in the body work cooperatively as a team to maintain optimal redox balance in the cell/body. This balance is a key element in providing the necessary conditions for cell signalling, a vital process for regulation of the expression of various genes, stress adaptation and homeostasis maintenance in the body. Since ROS/RNS are considered to be important signalling molecules, their concentration is strictly regulated by the antioxidant defence network in conjunction with various transcription factors and vitagenes. In fact, activation of vitagenes via such transcription factors as Nrf2 leads to an additional synthesis of an array of protective molecules which can deal with increased ROS/RNS production. Therefore, it is a challenging task to develop a system of optimal antioxidant supplementation to help growing/productive birds maintain effective antioxidant defences and redox balance in the body. On the one hand, antioxidants, such as vitamin E, or minerals (e.g., Se, Mn, Cu and Zn) are a compulsory part of the commercial pre-mixes for poultry, and, in most cases, are adequate to meet the physiological requirements in these elements. On the other hand, due to the aforementioned commercially relevant stressors, there is a need for additional support for the antioxidant system in poultry. This new direction in improving antioxidant defences for poultry in stress conditions is related to an opportunity to activate a range of vitagenes (via Nrf2-related mechanisms: superoxide dismutase, SOD; heme oxygenase-1, HO-1; GSH and thioredoxin, or other mechanisms: Heat shock protein (HSP)/heat shock factor (HSP), sirtuins, etc.) to maximise internal AO protection and redox balance maintenance. Therefore, the development of vitagene-regulating nutritional supplements is on the agenda of many commercial companies worldwide.

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“…This quality control system protects the proteome by regulating the synthesis, folding, and trafficking of native proteins to their subcellular destination as well as the refolding and degradation of misfolded species. As such, molecular chaperones act at every step of the amyloid formation and clearance process (Balchin et al, 2016;Kampinga and Craig, 2010;Rosenzweig et al, 2019;Saibil, 2013;Wentink et al, 2019).…”

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confidence: 99%

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

Nachman

Wentink

Madiona

et al. 2019

Preprint

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The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease and other Tauopathies. Molecular chaperones are known for their function in maintaining protein homeostasis by preventing the formation or promoting the disaggregation of amorphous and amyloid protein aggregates. Here we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. This function is mediated by the core chaperone Hsc70, assisted by specific co-chaperones, in particular class B J-domain proteins and an Hsp110-type NEF. Recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell culture were processed by the Hsp70 disaggregation machinery, demonstrating the ability of this machinery to recognize a broad range of Tau aggregates. Chaperone treatment released monomeric, and small oligomeric Tau species, which induced the aggregation of self-propagating Tau species in a Tau cell culture model. We infer from these results that the activity of the Hsp70 disaggregation machinery is a double-sided sword as it attempts to eliminate Tau amyloids but with the price of generating new seeds. The Hsp70 disaggregase therefore has a crucial function in the Tau propagation cycle, rendering it a potential drug target in Tauopathies.

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The Hsp70 chaperone network

Cited by 798 publications

References 167 publications

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

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