Telling right from wrong in life — cellular quality control

Stoecklin, Georg; Bukau, Bernd

doi:10.1038/nrm3662

Cited by 9 publications

(7 citation statements)

References 16 publications

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“…Instead we observe a mixture of soluble oligomers in the middle of the gradient (Fig. 1b, tube II, fractions [6][7][8][9][10][11] while fibrils move to the bottom (tube I, fraction 12).…”

Section: Resultsmentioning

confidence: 91%

Human chaperones untangle fibrils of the Alzheimer protein Tau

Ferrari

Wezel

et al. 2018

Preprint

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Alzheimer's Disease is the most common neurodegenerative disorder. A hallmark of this disease is aggregation of the protein Tau into fibrillar tangles, which is ultimately linked to neuronal death 1, 2 . Oligomeric precursors of Tau fibrils are suspected to be the neurotoxic agent while fibrils themselves may be less harmful end products of the aggregation process 3, 4 . Evolutionary conserved families of molecular chaperones maintain protein homeostasis in healthy cells, preventing aggregation 5, 6 . Here, we investigate whether such chaperones could possibly reverse the aggregation reaction and dissolve Tau fibrils. Indeed we find that the human Hsp70 chaperone system disaggregates Tau fibrils. Both the bacterial and human Hsp70 chaperone systems disassemble fibril superstructures assembled of several fibril strands into single fibrils, indicating that this is an evolutionary conserved capacity of the Hsp70 system. However, further disaggregation of Tau fibrils into oligomers and even monomers is reserved to the human homologue. Thus, although bacteria possess an effective machinery to dissolve amorphous aggregates 7-9 , we see that they do not have the means to disaggregate fibrils. Fibrillar aggregates, therefore, require different chaperone systems than amorphous aggregates, and this is a property acquired by Hsp70 during evolution. This makes the Hsp70 system an interesting target for novel drug strategies in Alzheimer.

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“…Instead we observe a mixture of soluble oligomers in the middle of the gradient (Fig. 1b, tube II, fractions [6][7][8][9][10][11] while fibrils move to the bottom (tube I, fraction 12).…”

Section: Resultsmentioning

confidence: 91%

Human chaperones untangle fibrils of the Alzheimer protein Tau

Ferrari

Wezel

et al. 2018

Preprint

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“…These findings in such phylogenetically distant genetic systems suggest that the compartmentalization of oxidized RNA has fundamental significance. Compartmentalization of DNA and protein quality control is well documented and believed to have several functions: the sequestration of damaged molecules prevents them from interfering with the processes in which they normally function; it prevents the degradation or attempted repair of undamaged substrates; and, finally, compartmentalization could enhance local concentrations of substrate molecules and quality control factors to establish thermodynamic parameters that favour forward reactions, for example, in repair or degradation (Adjibade and Mazroui, 2014;Stoecklin and Bukau, 2013;Walters and Parker, 2014). Our results open avenues to study the role of compartmentalization in RNA quality control.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular quality control systems specifically recognize oxidized molecules and subject them to repair, sequestration or degradation (Stoecklin and Bukau, 2013). Quality control systems have been characterized for oxidized DNA, proteins and lipids, but not for oxidized RNA (Wurtmann and Wolin, 2009).…”

Section: Introductionmentioning

confidence: 99%

Localized control of oxidized RNA

Zhan

Dhaliwal

Adjibade

et al. 2015

Journal of Cell Science

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The oxidation of biological molecules by reactive oxygen species (ROS) can render them inactive or toxic. This includes the oxidation of RNA, which appears to underlie the detrimental effects of oxidative stress, aging and certain neurodegenerative diseases. Here, we investigate the management of oxidized RNA in the chloroplast of the green alga Chlamydomonas reinhardtii. Our immunofluorescence microscopy results reveal that oxidized RNA (with 8-hydroxyguanine) is localized in the pyrenoid, a chloroplast microcompartment where CO 2 is assimilated by the Calvin cycle enzyme Rubisco. Results of genetic analyses support a requirement for the Rubisco large subunit (RBCL), but not Rubisco, in the management of oxidized RNA. An RBCL pool that can carry out such a 'moonlighting' function is revealed by results of biochemical fractionation experiments. We also show that human (HeLa) cells localize oxidized RNA to cytoplasmic foci that are distinct from stress granules, processing bodies and mitochondria. Our results suggest that the compartmentalization of oxidized RNA management is a general phenomenon and therefore has some fundamental significance.

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“…Typical strategies include targeting misfolded, unfolded, and aggregated polypeptides for reactivation or degradation (Bukau and Horwich, 1998; Wickner et al, 1999; Stoecklin and Bukau, 2013). Misfolded proteins are generated during polypeptide elongation and as a complication of environmental stress (Powers and Balch, 2013).…”

Section: Introductionmentioning

confidence: 99%

The Protein Chaperone ClpX Targets Native and Non-native Aggregated Substrates for Remodeling, Disassembly, and Degradation with ClpP

LaBreck

May

Viola

et al. 2017

Front. Mol. Biosci.

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ClpX is a member of the Clp/Hsp100 family of ATP-dependent chaperones and partners with ClpP, a compartmentalized protease, to degrade protein substrates bearing specific recognition signals. ClpX targets specific proteins for degradation directly or with substrate-specific adaptor proteins. Native substrates of ClpXP include proteins that form large oligomeric assemblies, such as MuA, FtsZ, and Dps in Escherichia coli. To remodel large oligomeric substrates, ClpX utilizes multivalent targeting strategies and discriminates between assembled and unassembled substrate conformations. Although ClpX and ClpP are known to associate with protein aggregates in E. coli, a potential role for ClpXP in disaggregation remains poorly characterized. Here, we discuss strategies utilized by ClpX to recognize native and non-native protein aggregates and the mechanisms by which ClpX alone, and with ClpP, remodels the conformations of various aggregates. We show that ClpX promotes the disassembly and reactivation of aggregated Gfp-ssrA through specific substrate remodeling. In the presence of ClpP, ClpX promotes disassembly and degradation of aggregated substrates bearing specific ClpX recognition signals, including heat-aggregated Gfp-ssrA, as well as polymeric and heat-aggregated FtsZ, which is a native ClpXP substrate in E. coli. Finally, we show that ClpX is present in insoluble aggregates and prevents the accumulation of thermal FtsZ aggregates in vivo, suggesting that ClpXP participates in the management of aggregates bearing ClpX recognition signals.

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Telling right from wrong in life — cellular quality control

Cited by 9 publications

References 16 publications

Human chaperones untangle fibrils of the Alzheimer protein Tau

Human chaperones untangle fibrils of the Alzheimer protein Tau

Localized control of oxidized RNA

The Protein Chaperone ClpX Targets Native and Non-native Aggregated Substrates for Remodeling, Disassembly, and Degradation with ClpP

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