Eisele, F. & Wolf, D. H. Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett. 582, 4143-4146

Institut für Biochemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
FEBS letters (Impact Factor: 3.17). 12/2008; 582(30):4143-6. DOI: 10.1016/j.febslet.2008.11.015
Source: PubMed


Protein quality control and subsequent elimination of terminally misfolded proteins occurs via the ubiquitin-proteasome system. Tagging of misfolded proteins with ubiquitin for degradation depends on a cascade of reactions involving an ubiquitin activating enzyme (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). While ubiquitin ligases responsible for targeting misfolded secretory proteins to proteasomal degradation (ERAD) have been uncovered, no such E3 enzymes have been found for elimination of misfolded cytoplasmic proteins in yeast. Here we report on the discovery of Ubr1, the E3 ligase of the N-end rule pathway, to be responsible for targeting misfolded cytosoplasmic protein to proteasomal degradation.

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Available from: Dieter Heinrich Wolf, Dec 20, 2013
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    • "Another recent study questions the proposed role of ubiquitination as essential, general sorting signal [14]. This is based on the observation that the misfolded substrate tGnd1-GFP, which is ubiquitinated in vivo almost exclusively by San1 and Ubr1, the major E3 ubiquitin ligases acting in protein quality control [24] [25] [26], accumulates at both INQ (JUNQ) and CytoQ deposits even in a non-ubiquitinated state in ubr1 san1 "
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    ABSTRACT: An evolutionary conserved response of cells to proteotoxic stress is the organized sequestration of misfolded proteins into subcellular deposition sites. In Saccharomyces cerevisiae three major sequestration sites for misfolded proteins exist, IPOD, INQ (former JUNQ) and CytoQ. IPOD is perivacuolar and predominantly sequesters amyloidogenic proteins. INQ and CytoQs are stress-induced deposits for misfolded proteins residing in the nucleus and the cytosol, respectively, and requiring cell compartment-specific aggregases, nuclear Btn2 and cytosolic Hsp42, for formation. The organized aggregation of misfolded proteins is proposed to serve several purposes collectively increasing cellular fitness and survival under proteotoxic stress. These include (i) shielding of cellular processes from interference by toxic protein conformers; (ii) reducing the substrate burden for protein quality control systems upon immediate stress; (iii) orchestrating chaperone and protease functions for efficient repair or degradation of damaged proteins; this involves initial extraction of aggregated molecules via the Hsp70/Hsp104 bi-chaperone system followed by either refolding or proteasomal degradation or removal of entire aggregates by selective autophagy (aggrephagy) involving the adaptor protein Cue5; (iv) enabling asymmetric retention of protein aggregates during cell division, thereby allowing for damage clearance in daughter cells. Regulated protein aggregation thus serves cytoprotective functions vital for the maintenance of cell integrity and survival even under adverse stress conditions and during aging.
    Journal of Molecular Biology 02/2015; 76(7). DOI:10.1016/j.jmb.2015.02.006 · 4.33 Impact Factor
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    • "Beyond the RNF126 and CHIP pathways, other cytosolic quality control systems have been characterized primarily in yeast. Here, the ligases Ubr1, San1, and Hul5 appear to be the main cytosolic quality control ligases, while Ltn1 operates at stalled ribosomes (Bengtson and Joazeiro, 2010; Eisele and Wolf, 2008; Gardner et al., 2005; Heck et al., 2010). These pathways are relatively poorly understood at this time with respect to their client range, mechanism of client recognition, and potential interaction with chaperones. "
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    ABSTRACT: Approximately 30% of eukaryotic proteins contain hydrophobic signals for localization to the secretory pathway. These proteins can be mislocalized in the cytosol due to mutations in their targeting signals, certain stresses, or intrinsic inefficiencies in their translocation. Mislocalized proteins (MLPs) are protected from aggregation by the Bag6 complex and degraded by a poorly characterized proteasome-dependent pathway. Here, we identify the ubiquitin ligase RNF126 as a key component of the MLP degradation pathway. In vitro reconstitution and fractionation studies reveal that RNF126 is the primary Bag6-dependent ligase. RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients. Interfering with RNF126 recruitment in vitro prevents ubiquitination, and RNF126 depletion in cells partially stabilizes a Bag6 client. Bag6-dependent ubiquitination can be recapitulated with purified components, paving the way for mechanistic analyses of downstream steps in this cytosolic quality control pathway.
    Molecular Cell 06/2014; 55(2). DOI:10.1016/j.molcel.2014.05.025 · 14.02 Impact Factor
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    • "In yeast, cytosolic Hsp70, Ssa1 is required for folding, refolding and ubiquitin-mediated degradation of substrates. The primary degradation pathway (UPS) mediated by Ssa1 involves the E3 ligase Ubr1 and San1 [86] [87] [88] and ER/Nuclear envelope localized E3 ligase Doa10 for ERAD-C pathway [89]. But what determines the condition in which degradation will be favored over refolding or viceversa is still not clear. "
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    ABSTRACT: Proteins are always at risk inside the cellular environment. Stress enhances the propensity of protein misfolding. Cell has evolved dynamic machinery called protein quality control (PQC) to minimize the risk of protein misfolding. The efficiency of PQC decreases during ageing; and the tendency of misfolded protein accumulation reduces the lifespan of an organism. Cell reduces the flux of misfolded proteins by refolding, degradation, or by se-questering into inclusions. Several evidences support the involvement of molecular chaperones that act as primary cellular defense. Among these, Hsp70 protein plays the prime function in maintaining PQC. Hsp70 has the unique ability to attune its function in response to the cellular need. From folding to degradation , solubilising aggregates, refolding of damaged proteins, and preventing harmful assemblage of protein inclusions, Hsp70 portrays a wide array of functions. These functions are attributed by the chaperone alone or along with its co-chaperones, Hsp40 (J-proteins), Hsp110 (NEF's) or Hsp104. Recent studies indicate Hsp70 as a degradation chaperone that efficiently facilitates in clearance of misfolded proteins. We discuss here the diverse roles of Heat Shock Protein 70 (Hsp70) chaperone in client fate determination. Moreover , we focus on the strategies cell undertake when major chaperone functions are compromised due to targeted inhibition or particular stress conditions. In the light of these findings, we discuss how chaperone modulation can evolve as an effective strategy to combat various neuropathies, ion channel misfolding diseases and selective parasitic maladies.
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