Kostova, Z., Tsai, Y. C. & Weissman, A. M. Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin. Cell Dev. Biol. 18, 770-779

Laboratory of Protein Dynamics and Signaling, Building 560 Room 22-103, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, MD 21702, United States.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 01/2008; 18(6):770-9. DOI: 10.1016/j.semcdb.2007.09.002
Source: PubMed


Endoplasmic reticulum-associated degradation (ERAD) represents the primary means of quality control within the secretory pathway. Critical to this process are ubiquitin protein ligases (E3s) which, together with ubiquitin conjugating enzymes (E2s), mediate the ubiquitylation of proteins targeted for degradation from the ER. In this chapter we review our knowledge of both Saccharomyces cerevisiae and mammalian ERAD ubiquitin ligases. We focus on recent insights into these E3s, their associated proteins and potential mechanisms of action.

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    • "Thus, transport of the substrates across the ER membrane to the cytosol, known as dislocation or retrotranslocation , is a key step in ERAD. It is well established that ER membrane-anchored protein complex centered on an E3 ubiquitin ligase integrates identification, dislocation, ubiquitination, and proteasomal degradation of unwanted ER proteins during ERAD [5] [6]. Over a dozen of E3 ubiquitin ligases have now been found to function in ERAD [5e11]. "
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    ABSTRACT: Misfolded proteins or orphan subunits of protein complexes are removed from the endoplasmic reticulum (ER) by ER-associated degradation (ERAD). ERAD requires dislocation, also known as retrotranslocation, of those unwanted proteins from the ER lumen to the cytosol for destruction by the proteasomes. Over one hundred ERAD component proteins have been identified but their role in dislocation remain poorly understood. Here we assessed the requirement of ERAD components for dislocation of NHK in live cells using our recently developed dislocation-induced reconstituted GFP (drGFP) assay. RNAi revealed that 12 out of 21 ERAD components examined are required for efficient dislocation of NHK among which Hrd1, Sel1L, GRP94 and p97/VCP are critically required. In addition, knockdown of 7 of the 21 components enhanced NHK dislocation. This study uncovers a complex functional network of proteins required for NHK dislocation. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 458(2). DOI:10.1016/j.bbrc.2015.01.133 · 2.30 Impact Factor
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    • "The ubiquitination of ERAD substrates, especially those lacking N-glycan degradation signals, by the Hrd1 complex requires two additional adapters: U1-Snp1 associating-1 (Usa1; HERP in mammals), an ER membrane protein containing a ubiquitin-like (UBL) motif near it N-terminus and two predicted transmembrane domains in the middle, and Der1 (degradation in the ER; Derlins for Der1-like proteins in mammals), another integral ER membrane protein with four transmembrane segments (Kostova et al., 2007). Usa1 is thought to regulate the stability and/or oligomerization of Hrd1 and to recruit Der1 to the Hrd1 complex (Carvalho et al., 2006, 2010; Horn et al., 2009; Carroll and Hampton, 2010), while Der1 is believed to function either as a receptor for soluble non-glycosylated ERAD substrates or a potential retrotranslocation channel (Lilley and Ploegh, 2004; Ye et al., 2004; Kanehara et al., 2010). "
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    ABSTRACT: A correct three-dimensional structure is crucial for the physiological functions of a protein, yet the folding of proteins to acquire native conformation is a fundamentally error-prone process. Eukaryotic organisms have evolved a highly conserved endoplasmic reticulum-mediated protein quality control (ERQC) mechanism to monitor folding processes of secretory and membrane proteins, allowing export of only correctly folded proteins to their physiological destinations, retaining incompletely/mis-folded ones in the ER for additional folding attempts, marking and removing terminally misfolded ones via a unique multiple-step degradation process known as ER-associated degradation (ERAD). Most of our current knowledge on ERQC and ERAD came from genetic and biochemical investigations in yeast and mammalian cells. Recent studies in the reference plant Arabidopsis thaliana uncovered homologous components and similar mechanisms in plants for monitoring protein folding and for retaining, repairing, and removing misfolded proteins. These studies also revealed critical roles of the plant ERQC/ERAD systems in regulating important biochemical/physiological processes, such as abiotic stress tolerance and plant defense. In this review, we discuss our current understanding about the molecular components and biochemical mechanisms of the plant ERQC/ERAD system in comparison to yeast and mammalian systems.
    Frontiers in Plant Science 04/2014; 5:162. DOI:10.3389/fpls.2014.00162 · 3.95 Impact Factor
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    • "A number of ER luminal chaperones and lectins initially recognize and deliver ERAD substrates to membrane export sites (4,5). Here, a multi-protein complex, led by ER-associated E3 ubiquitin ligases, such as HRD1, gp78, TEB4 or RMA1, marks the misfolded protein with ubiquitin (6,7), an event also favoring the dislocation into the cytosol, where the 26S proteasome resides. The polyubiquitin chain, in fact, offers a handle to p97, an AAA-ATPase that eventually provides the driving force to eradicate ERAD substrates from the membrane (8–10). "
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    ABSTRACT: Many membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated into the cytosol and degraded by the proteasome. In applying rigid rules, however, quality control sometimes discharges proteins that, even though defective, retain their function. The unnecessary removal of such proteins represents the pathogenetic hallmark of diverse genetic diseases, with the case of ΔF508 mutant of CFTR being probably the best known example. Recently, the inappropriate proteasomal degradation of skeletal muscle sarcoglycans (α, β, γ and δ) with missense mutation has been proposed to be at the bases of mild-to-severe forms of limb girdle muscular dystrophy (LGMD) known as type 2D, 2E, 2C and 2F, respectively. The quality control pathway responsible for sarcoglycan mutant disposal, however, is so far unexplored. Here we reveal key components of the degradative route of V247M α-sarcoglycan mutant, the second most frequently reported mutation in LGMD-2D.The disclosure of the pathway, which is led by the E3 ligases HRD1 and RFP2, permits to identify new potential druggable targets of a disease for which no effective therapy is at present available. Notably, we show that the pharmacological inhibition of HRD1 activity rescues the expression of V247-α-sarcoglycan both in a heterologous cell model and in myotubes derived from a LGMD-2D patient carrying the L31P/V247M mutations. This represents the first evidence that the activity of E3 ligases, the enzymes in charge of mutant fate, can be eligible for drug interventions to treat sarcoglycanopathy.
    Human Molecular Genetics 02/2014; 23(14). DOI:10.1093/hmg/ddu088 · 6.39 Impact Factor
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