Pathways of cellular proteostasis in aging and disease

Klaips, Courtney L.; Jayaraj, Gopal Gunanathan; Fu, Hartl

doi:10.1083/jcb.201709072

Cited by 661 publications

(605 citation statements)

References 187 publications

(262 reference statements)

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“…Maintenance of the nuclear proteome is important to preserve genome integrity. Indeed, many age-related neurodegenerative diseases, which are characterized by the presence of nuclear protein aggregates and proteostasis impairment, are also linked to genome instability (Shibata & Morimoto, 2014;Klaips et al, 2018). Although nuclear protein aggregation induces mutagenesis and DNA damage (Shor et al, 2013;Shibata & Morimoto, 2014), we do not understand how these processes are linked at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin

et al. 2019

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Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation‐prone proteins in cells is defective ribosomal products ( DR iPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DR iPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid–liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DR iPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress‐inducible overflow compartments for DR iPs. If DR iPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival.

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Section: Introductionmentioning

confidence: 99%

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin

et al. 2019

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“…Trafficking of substances out of cells is also a process for ridding cells of junk material and molecules that have misfolded and cannot be refolded or degraded. Ensuring protein homeostasis, or proteostasis, requires precise control of not only synthesis and folding but also clearance of misfolded molecules, and cells have evolved an adaptive network of mechanisms involving molecular chaperones and their regulators to combat this (11).…”

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confidence: 99%

Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways

et al. 2019

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During physiologic stresses, like micronutrient starvation, infection, and cancer, the cytosolic moonlighting protein glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is trafficked to the plasma membrane (PM) and extracellular milieu (ECM). Our work demonstrates that GAPDH mobilized to the PM, and the ECM does not utilize the classic endoplasmic reticulum–Golgi route of secretion; instead, it is first selectively translocated into early and late endosomes from the cytosol via microautophagy. GAPDH recruited to this common entry point is subsequently delivered into multivesicular bodies, leading to its membrane trafficking through secretion via exosomes and secretory lysosomes. We present evidence that both pathways of GAPDH membrane trafficking are up‐regulated upon iron starvation, potentially by mobilization of intracellular calcium. These pathways also play a role in clearance of misfolded intracellular polypeptide aggregates. Our findings suggest that cells build in redundancy for vital cellular pathways to maintain micronutrient homeostasis and prevent buildup of toxic intracellular misfolded protein refuse.—Chauhan, A. S., Kumar, M., Chaudhary, S., Dhiman, A., Patidar, A., Jakhar, P., Jaswal, P., Sharma, K., Sheokand, N., Malhotra, H., Raje, C. I., Raje. M. Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways. FASEB J. 33, 5626–5640 (2019). http://www.fasebj.org

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“…To offset the cellular stresses associated with these toxic species, all cells harbor molecular chaperones which reduce the misfolded protein burden. 1, 2 Most molecular chaperones, such as Hsp70, bind linear arrays of amino acids with overall hydrophobic character, thereby limiting access of aggregation-prone motifs to the aqueous environment in the cell. 3–5 The binding of protein clients to Hsp70 is driven by cycles of ATP binding and hydrolysis: Hsp70 in the ATP bound conformation exhibits a high on- and off-rate for protein binding, but hydrolysis and conversion to the ADP-bound conformation favors protein binding because a C-terminal “lid” domain closes over the substrate binding pocket.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of esterified Hsp70 agonists in cellular models of protein aggregation and folding

Chiang

Liang

Dominguez-Meijide

et al. 2019

Bioorganic & Medicinal Chemistry

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Over-expression of the Hsp70 molecular chaperone prevents protein aggregation and ameliorates neurodegenerative disease phenotypes in model systems. We identified an Hsp70 activator, MAL1–271, that reduces α-synuclein aggregation in a Parkinson’s Disease model. We now report that MAL1–271 directly increases the ATPase activity of a eukaryotic Hsp70. Next, twelve MAL1–271 derivatives were synthesized and examined in a refined α-synuclein aggregation model as well as in an assay that monitors maturation of a disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutant, which is also linked to Hsp70 function. Compared to the control, MAL1–271 significantly increased the number of cells lacking α-synuclein inclusions and increased the steady-state levels of the CFTR mutant. We also found that a nitrile-containing MAL1–271 analog exhibited similar effects in both assays. None of the derivatives exhibited cellular toxicity at concentrations up to 100µM, nor were cellular stress response pathways induced. These data serve as a gateway for the continued development of a new class of Hsp70 agonists with efficacy in these and potentially other disease models.

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Pathways of cellular proteostasis in aging and disease

Abstract: Klaips et al. outline the pathways and molecular mechanisms of cellular protein homeostasis, or proteostasis, and discuss how a decline in proteostasis during aging contributes to disease.

Cited by 661 publications

References 187 publications

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin

Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways

Synthesis and evaluation of esterified Hsp70 agonists in cellular models of protein aggregation and folding

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