Ubiquitylation as a Quality Control System for Intracellular Proteins

Abstract

Quality control of intracellular proteins is essential for cellular homeostasis. Molecular chaperones recognize and contribute to the refolding of misfolded or unfolded proteins, whereas the ubiquitin-proteasome system mediates the degradation of such abnormal proteins. Ubiquitin-protein ligases (E3s) determine the substrate specificity for ubiquitylation and have been classified into HECT and RING-finger families. More recently, however, U-box proteins, which contain a domain (the U box) of about 70 amino acids that is conserved from yeast to humans, have been identified as a new type of E3. The prototype U-box protein, yeast Ufd2, was identified as a ubiquitin chain assembly factor (E4) that cooperates with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and an E3 to catalyze the formation of a ubiquitin chain on artificial substrates. Yeast Ufd2 is functionally implicated in cell survival under stressful conditions. This review addresses recent progress in characterization of the role of E3 enzymes, especially that of U-box proteins, in quality control of intracellular proteins.

Heat Shock Protein Cognate 70-4 and an E3 Ubiquitin Ligase, CHIP, Mediate Plastid-Destined Precursor Degradation through the Ubiquitin-26S Proteasome System inArabidopsis

“…Unfolded proteins in an aqueous environment tend to form highly cytotoxic nonspecific aggregates if they accumulate to high levels (Wickner et al, 1999;Hartl and Hayer-Hartl, 2002;Hatakeyama and Nakayama, 2003;Esser et al, 2004). Therefore, the amount of unfolded plastid precursors must be precisely Regulation of Precursor Levels by Hsc70-4 and CHIP 3997 maintained below a threshold at which nonspecific protein aggregates can form.…”

“…In contrast with Hsc70s, the ubiquitin/proteasome system (UPS) removes unfolded or misfolded proteins through protein degradation (Esser et al, 2004). In this process, misfolded proteins are marked with polyubiquitin chain by an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase (Hershko et al, 2000;Cyr et al, 2002;Hatakeyama and Nakayama, 2003;Esser et al, 2004). Molecular chaperones also play a critical role in the UPS (Esser et al, 2004).…”

“…Eukaryotic cells have a protein quality control (PQC) mechanism to constantly monitor the quality of newly synthesized proteins and preexisting proteins and to actively remove unfolded or misfolded proteins (Hartl and Hayer-Hartl, 2002;Hatakeyama and Nakayama, 2003;Esser et al, 2004). It is reported that as much as 30% of newly synthesized proteins are immediately degraded by the PQC system because of a problem in protein folding (Schubert et al, 2000).…”

“…Therefore, posttranslational targeting to endosymbiotic organelles requires that precursor levels be maintained within limits that do not result in nonspecific aggregate formation. At the same time, the cytosolic regulatory mechanism must not jeopardize the supply of sufficient amounts of proteins to the organelles.Eukaryotic cells have a protein quality control (PQC) mechanism to constantly monitor the quality of newly synthesized proteins and preexisting proteins and to actively remove unfolded or misfolded proteins (Hartl and Hayer-Hartl, 2002;Hatakeyama and Nakayama, 2003;Esser et al, 2004). It is reported that as much as 30% of newly synthesized proteins are immediately degraded by the PQC system because of a problem in protein folding (Schubert et al, 2000).…”

“…By contrast, in the absence of the guidance factor binding to the transit peptide, Hsc70-4 may alternatively interact with CHIP, which in turn leads to the degradation of precursors. Consistent with this hypothesis, RbcS[T1A]:GFP and its mutant derivatives that are slowly imported into chloroplasts in protoplasts (Lee et al, 2006) were highly susceptible to Hsc70-4-mediated degradation.Unfolded proteins in an aqueous environment tend to form highly cytotoxic nonspecific aggregates if they accumulate to high levels (Wickner et al, 1999;Hartl and Hayer-Hartl, 2002;Hatakeyama and Nakayama, 2003;Esser et al, 2004). Therefore, the amount of unfolded plastid precursors must be precisely Regulation of Precursor Levels by Hsc70-4 and CHIP 3997 maintained below a threshold at which nonspecific protein aggregates can form.…”