Article

Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation

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: 5.97). 01/2008; 18(6):770-9. DOI: 10.1016/j.semcdb.2007.09.002
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
90 Views
  • Source
    • "In Saccharomyces cerevisiae, ubiquitination of an HMGCR orthologue, Hmg2p, is mediated by the polytopic RING finger ubiquitin ligase Hrd1p/Der3p (Hampton et al., 1996), one of only two S. cerevisiae ERAD E3s (reviewed in Kostova et al., 2007). In mammals there are >5, and possibly >20, ER-resident RING finger E3s (Neutzner et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endoplasmic reticulum (ER) resident enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase) catalyzes the rate-limiting step in sterol production and is the therapeutic target of statins. Understanding HMG-CoA reductase regulation has tremendous implications for atherosclerosis. HMG-CoA reductase levels are regulated in response to sterols both transcriptionally, through a complex regulatory loop involving the ER Insig proteins, and posttranslationally by Insig-dependent protein degradation by the ubiquitin-proteasome system. The ubiquitin ligase (E3) gp78 has been implicated in the sterol-regulated degradation of HMG-CoA reductase and Insig-1 through ER-associated degradation (ERAD). More recently, a second ERAD E3, TRC8, has also been reported to play a role in the sterol-accelerated degradation of HMG-CoA reductase. We have interrogated this network in gp78(-/-) mouse embryonic fibroblasts and also assessed two fibroblast cell lines using RNAi. While we consistently observe involvement of gp78 in Insig-1 degradation, no substantive evidence to support roles for either gp78 or TRC8 in the robust sterol-accelerated degradation of HMG-CoA reductase was found. We discuss factors that might lead to such discrepant findings. Our results suggest a need for additional studies before definitive mechanistic conclusions are drawn that might set the stage for development of drugs to manipulate gp78 function in metabolic disorders.
    Molecular biology of the cell 10/2012; 23(23). DOI:10.1091/mbc.E12-08-0631 · 5.98 Impact Factor
  • Source
    • "Considering that the yeast homolog genes of UBC32 and HRD3A belong to different ERAD complexes ( Doa10 and Hrd1 complexes ) , and the Hrd1 complex mainly recognize ERAD - L substrates , while Doa10 mainly contributes to the ERAD - M and ERAD - C sub - strates ( Kostova et al . , 2007 ) , the diversification of the substrate ranges of UBC32 and HRD3A is reasonable . From another aspect , there are already some examples that ERAD may lead to favorable effects for organisms under specific situations . For example , mutations in yeast ubc6 suppress the temperature - sensitive phenotype of the sec61 mutant , which leads "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plants modify their growth and development to protect themselves from detrimental conditions by triggering a variety of signaling pathways, including the activation of the ubiquitin-mediated protein degradation pathway. Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important aspect of the ubiquitin-proteasome system, but only a few of the active ERAD components have been reported in plants. Here, we report that the Arabidopsis thaliana ubiquitin-conjugating enzyme, UBC32, a stress-induced functional ubiquitin conjugation enzyme (E2) localized to the ER membrane, connects the ERAD process and brassinosteroid (BR)-mediated growth promotion and salt stress tolerance. In vivo data showed that UBC32 was a functional ERAD component that affected the stability of a known ERAD substrate, the barley (Hordeum vulgare) powdery mildew O (MLO) mutant MLO-12. UBC32 mutation caused the accumulation of bri1-5 and bri1-9, the mutant forms of the BR receptor, BRI1, and these mutant forms subsequently activated BR signal transduction. Further genetic and physiological data supported the contention that UBC32 plays a role in the BR-mediated salt stress response and that BR signaling is necessary for the plant to tolerate salt. Our data indicates a possible mechanism by which an ERAD component regulates the growth and stress response of plants.
    The Plant Cell 01/2012; 24(1):233-44. DOI:10.1105/tpc.111.093062 · 9.58 Impact Factor
  • Source
    • "Because CHIP may interact with the E2 UbcH13/Uev1a, a heterodimeric E2 enzyme that exclusively forms K63-linked ubiquitin chains (Windheim et al., 2008; Xu et al., 2008), we suggest that laforin and malin could form a macrocomplex with CHIP and UbcH13/Uev1a that would be responsible for the K63-linked ubiquitination of specific substrates. In this way, malin would resemble parkin, an E3-ubiquitin ligase related to Parkinson disease, because it was described that parkin mediated the K63-linked ubiquitination of misfolded DJ-1 (Olzmann et al., 2007), synphilin-1 (Lim et al., 2005), and ␣-synuclein (Liu et al., 2007), promoting in this way their aggregation, and that the action of parkin was possibly mediated by its interaction with CHIP and UbcH13/Uev1a [(Lim et al., 2006), (Yoshida, 2007), (Kostova et al., 2007)]. Alternatively, laforin and malin could interact directly with UbcH13/Uev1a. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lafora progressive myoclonus epilepsy is a fatal neurodegenerative disorder caused by defects in the function of at least two proteins: laforin, a dual-specificity protein phosphatase, and malin, an E3-ubiquitin ligase. In this study, we report that a functional laforin-malin complex promotes the ubiquitination of AMP-activated protein kinase (AMPK), a serine/threonine protein kinase that acts as a sensor of cellular energy status. This reaction occurs when any of the three AMPK subunits (alpha, beta, and gamma) are expressed individually in the cell, and it also occurs on AMPK beta when it is part of a heterotrimeric complex. We also report that the laforin-malin complex promotes the formation of K63-linked ubiquitin chains, which are not involved in proteasome degradation. On the contrary, this modification increases the steady-state levels of at least AMPK beta subunit, possibly because it leads to the accumulation of this protein into inclusion bodies. These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.
    Molecular biology of the cell 08/2010; 21(15):2578-88. DOI:10.1091/mbc.E10-03-0227 · 5.98 Impact Factor
Show more

Preview

Download
0 Downloads
Available from