Two distinct mechanisms operate in the reactivation of heat-denatured proteins by the mitochondrial Hsp70/Mdj1p/Yge1p chaperone system

Kubo, Yuko; Tsunehiro, Takeshi; Nishikawa, Shuh-ichi; Nakai, Masaaki; Ikeda, Eri; Toh‐e, Akio; Morishima, Nobuhiro; Shibata, Takehiko; Endo, Toshiya

doi:10.1006/jmbi.1998.2465

Cited by 36 publications

(23 citation statements)

References 38 publications

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“…As shown in Fig. 4e, Hsp70 efficiently reduces thermally induced aggregation of citrate synthase at 43 °C in the absence of ATP, in a concentration-dependent manner, confirming that it acts as a chaperone 23 . Lysozyme, which has no known chaperone activity, does not effectively suppress thermally induced aggregation of citrate synthase (Fig.…”

supporting

confidence: 61%

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Zhai

Zhang

Hiesinger³

et al. 2008

Nature

186

218

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Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activityinduced neurodegeneration and injury-induced axonal degeneration 1,2 . Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heatshock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions. Injury-induced axonal degeneration is dramatically delayed in wallerian degeneration slow (Wld S ) mice, a mutant strain that over-expresses a chimaeric protein containing the NAD synthase NMNAT 3,4 . The Wld S chimaeric protein offers neuroprotection against axonal degeneration 2,5-7 as well as a variety of neurodegenerative conditions [8][9][10][11] . Wld S protein contains the amino (N)-terminal 70-amino-acid fragment of ubiquitination factor E4B ©2008 Nature Publishing GroupCorrespondence and requests for materials should be addressed to R.G. 4,14,15 . Drosophila contains only one NMNAT gene, whose overexpression delays axonal degeneration 2 . This study and our finding that NMNAT functions as a maintenance factor to protect against activity-induced neurodegeneration 1 suggest that NMNAT alone can protect against multiple neurodegenerative insults. Our recent finding that enzymatically inactive NMNAT retains neuroprotective capabilities also exposed a hitherto unknown molecular function 1 .To test if NMNAT is a general factor required for neuronal maintenance and protection, we first examined the effects of NMNAT overexpression in a Drosophila model for SCA1. Overexpression of wild-type NMNAT or enzyme-inactive NMNAT (NMNAT-WR) 1 suppresses the degenerative phenotypes induced by overexpression of Drosophila ataxin-1 (dAtx-1). It also offers moderate protection against the severe phenotypes caused by overexpression of human ataxin-1 with an expanded (82) poly-glutamine tract (hAtx-1[82Q]) 16 (Fig. 1). These findings, and the observations that NMNAT protects from axonal injury 2 , from photoreceptor injury caused by intense light, and that its loss c...

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supporting

confidence: 61%

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Zhai

Zhang

Hiesinger³

et al. 2008

Nature

186

218

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“…The poly-His tag was removed with thrombin (GE Healthcare). The purification of Ssa1 and Ydj1 was conducted as described previously, with several modifications (25,26). The cells were homogenized by a metal cone (Yasui Kikai, Osaka, Japan) using a Multi-Beads Shocker (Yasui Kikai, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Single-molecule Analyses of the Dynamics of Heat Shock Protein 104 (Hsp104) and Protein Aggregates

Okuda

Niwa

Taguchi

2015

Journal of Biological Chemistry

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Background:The process of disaggregation by heat shock protein 104 (Hsp104) and heat shock protein 70/40 (Hsp70/40) has not been elucidated. Results: We developed several methods to investigate the dynamics of Hsp104 at single-molecule levels. Conclusion: Statistical analyses revealed that Hsp70/40 affected the dynamics of Hsp104. Significance: Single-molecule approaches are a unique way to unravel the functional mechanisms of disaggregases.

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“…Analytical 12% sodium dodecyl sulfate (SDS)-PAGE followed by Coomassie blue staining was used to visualize the individual protein components of the Mss51-containing complexes. Replicas of both kinds of gels were used for protein transfer to a polyvinylidene difluoride membrane and immunodetection with anti-GST (Santa Cruz Biotechnology, CA) and anti-Mss51 (2) antibodies and with antibodies specific to Cox1 and Cox2 (Molecular Probes, OR), Cox14 (2), ShyI (32), Mdj1 (25), and Ssc1 (7). To obtain material for protein identification by mass spectrometry (MS), the concentrated GST pulldowns were separated on preparative native and denaturing PAGE systems and stained with Coomassie blue.…”

Section: Methodsmentioning

confidence: 99%

Mss51 and Ssc1 Facilitate Translational Regulation of Cytochrome c Oxidase Biogenesis

Fontanesi¹,

Soto

Horn

et al. 2010

Molecular and Cellular Biology

125

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The intricate biogenesis of multimeric organellar enzymes of dual genetic origin entails several levels of regulation. In Saccharomyces cerevisiae, mitochondrial cytochrome c oxidase (COX) assembly is regulated translationally. Synthesis of subunit 1 (Cox1) is contingent on the availability of its assembly partners, thereby acting as a negative feedback loop that coordinates COX1 mRNA translation with Cox1 utilization during COX assembly. The COX1 mRNA-specific translational activator Mss51 plays a fundamental role in this process. Here, we report that Mss51 successively interacts with the COX1 mRNA translational apparatus, newly synthesized Cox1, and other COX assembly factors during Cox1 maturation/assembly. Notably, the mitochondrial Hsp70 chaperone Ssc1 is shown to be an Mss51 partner throughout its metabolic cycle. We conclude that Ssc1, by interacting with Mss51 and Mss51-containing complexes, plays a critical role in Cox1 biogenesis, COX assembly, and the translational regulation of these processes.

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Two distinct mechanisms operate in the reactivation of heat-denatured proteins by the mitochondrial Hsp70/Mdj1p/Yge1p chaperone system

Cited by 36 publications

References 38 publications

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Single-molecule Analyses of the Dynamics of Heat Shock Protein 104 (Hsp104) and Protein Aggregates

Mss51 and Ssc1 Facilitate Translational Regulation of Cytochrome c Oxidase Biogenesis

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