A nucleus-based quality control mechanism for cytosolic proteins.
Intracellular quality control systems monitor protein conformational states. Irreversibly misfolded proteins are cleared through specialized degradation pathways. Their importance is underscored by numerous pathologies caused by aberrant proteins. In the cytosol, where most proteins are synthesized, quality control remains poorly understood. Stress-inducible chaperones and the 26S proteasome are known mediators but how their activities are linked is unclear. To better understand these mechanisms, a panel of model misfolded substrates was analyzed in detail. Surprisingly, their degradation occurs not in the cytosol but in the nucleus. Degradation is dependent on the E3 ubiquitin ligase San1p, known previously to direct the turnover of damaged nuclear proteins. A second E3 enzyme, Ubr1p, augments this activity but is insufficient by itself. San1p and Ubr1p are not required for nuclear import of substrates. Instead, the Hsp70 chaperone system is needed for efficient import and degradation. These data reveal a new function of the nucleus as a compartment central to the quality control of cytosolic proteins.
Prasad
Rupali
R
Temasek Life Sciences Laboratory and Department of Biological Sciences, National University of Singapore, Singapore 117604.
Kawaguchi
Shinichi
S
Ng
Davis T W
DT
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C500396:SAN1 protein, S cerevisiae; C066066:UBR1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
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