Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett

Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
FEBS letters (Impact Factor: 3.17). 04/2010; 584(7):1393-8. DOI: 10.1016/j.febslet.2009.12.047
Source: PubMed


The ubiquitin proteasome system (UPS) and macroautophagy (hereafter called autophagy) were, for a long time, regarded as independent degradative pathways with few or no points of interaction. This view started to change recently, in the light of findings that have suggested that ubiquitylation can target substrates for degradation via both pathways. Moreover, perturbations in the flux through either pathway have been reported to affect the activity of the other system, and a number of mechanisms have been proposed to rationalise the link between the UPS and autophagy. Here we critically review these findings and outline some outstanding issues that still await clarification.

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Available from: Viktor Korolchuk
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    • "Among proposed mechanisms the activation of endoplasmic reticulum (ER) stress, due to the accumulation of misfolded proteins that leads to the induction of the unfolded protein response (UPR), is an interesting candidate. These different mechanisms may not be mutually exclusive and may also be of different importance in different cell types or at different time-points after the proteasome is inhibited [11]. "
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    ABSTRACT: Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "Cross-talk between proteasomal degradation, autophagy and amino acid metabolism When proteasome degradation is compromised, cells adapt by inducing autophagy, and cross-talk events between the two cellular degradation pathways have been identified (Korolchuk et al., 2009). Both pathways contribute not only to protein homeostasis but also to amino acid homeostasis. "
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    ABSTRACT: Organisms have evolved mechanisms to cope with and adapt to unexpected challenges and harsh conditions. Unfolded or misfolded proteins represent a threat for cells and organisms, and the deposition of misfolded proteins is a defining feature of many age-related human diseases, including the increasingly prevalent neurodegenerative diseases. These protein misfolding diseases are devastating and currently cannot be cured, but are hopefully not incurable. In fact, the aggregation-prone and potentially harmful proteins at the origins of protein misfolding diseases are expressed throughout life, whereas the diseases are late onset. This reveals that cells and organisms are normally resilient to disease-causing proteins and survive the threat of misfolded proteins up to a point. This Commentary will outline the limits of the cellular resilience to protein misfolding, and discuss the possibility of pushing these limits to help cells and organisms to survive the threat of misfolding proteins and to avoid protein quality control catastrophes.
    Full-text · Article · Oct 2015 · Journal of Cell Science
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    • "In eukaryotic cells, misfolded and aggregated proteins are recognized and eliminated by protein degradation machineries such as the ubiquitin proteasome system (UPS) and autophagy (Korolchuk et al., 2010). p62/SQSTM1 (hereafter referred as to p62) has an important role in selective autophagy. "

    Full-text · Dataset · Aug 2015
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