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Journal of Biochemistry Advance Access originally published online on September 7, 2009
Journal of Biochemistry 2009 146(5):609-616; doi:10.1093/jb/mvp139
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

JB Minireview-Quality Control of the Cellular Protein Systems

Quality Control Against Misfolded Proteins in the Cytosol: A Network for Cell Survival

Hiroshi Kubota*

Department of Life Science, Faculty of Engineering and Resource Science, Akita University, Akita 010-8502, Japan

*To whom correspondence should be addressed. Tel/Fax: +81 18 889 3053, E-mail: hkubota{at}ipc.akita-u.ac.jp

Received July 7, 2009; Accepted August 5, 2009


  Abstract

Misfolded proteins are toxic to cells and the accumulation of toxic species can lead to protein misfolding diseases, such as neurodegenerative disorders. The toxicity of misfolded proteins is thought to result from the presence of exposed hydrophobic surfaces, which mediate unnecessary binding to normal proteins, interrupting essential interactions between cellular proteins. To prevent toxicity, quality control systems monitor protein folding and remove misfolded species in the cytosol. Molecular chaperones recognize and mask hydrophobic surfaces of misfolded monomers, and transfer them to the ubiquitin–proteasome system and chaperone-mediated autophagy. To eliminate soluble aggregates of misfolded proteins, the macroautophagy–lysosome system is thought to degrade proteasome-resistant toxic species. In addition, the microtubule-dependent transport system sequesters soluble oligomers/aggregates into inclusion bodies. These systems are regulated by stress-inducible transcription factors, cochaperones and other cofactors for the effective removal of toxic monomers and oligomers. This review explores the roles of protein quality control pathways and networks that control quality control activities in the cytosol, particularly focusing on recent progress in this field.

Key Words: autophagy–lysosome system, molecular chaperone, protein misfolding, protein quality control, ubiquitin–proteasome system

Abbreviations: ALS, amyotrophic lateral sclerosis; BAG, BCL2-associated athanogene; CCT, chaperonin containing t-complex polypeptide 1; CHIP, carboxy terminus of HSP70-binding protein; CMA, chaperone-mediated autophagy; FKBP, FK506-binding protein; HOP, HSP70/HSP90 organizing protein; HSC70, cognate of HSP70; HSE, heat shock element; HSF, heat shock factor; HSP, heat shock protein; MEF2D, myocyte enhancer factor 2D; NBR1, neighbour of BRCA1 gene 1; TPR, tetratricopeptide repeat; SOD1, superoxide dismutase 1


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