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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: 3.34). 04/2010; 584(7):1393-8. DOI: 10.1016/j.febslet.2009.12.047
Source: PubMed

ABSTRACT 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, Aug 22, 2015
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    • "The critical factors that direct a specific substrate to one degradation route or the other are incompletely understood. Protein degradations performed by the UPS and autophagy were regarded for a long time as complementary but separate mechanisms [3]. However, on the basis of recent studies, there are overlaps between them. "
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    ABSTRACT: The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family.
    BioMed Research International 06/2014; 2014(1):832704. DOI:10.1155/2014/832704 · 2.71 Impact Factor
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    • "Similarly, although few data show that proteasome genes are up-regulated during leaf senescence and that the proteasome can be important in the degradation of oxidized proteins under stress-induced conditions (Jain et al., 2008; Polge et al., 2009; Roberts et al., 2012), very little is known about its role during leaf senescence. In plants as in animals, the proteasome seems to be mainly involved in the turn-over of short-lived proteins whereas autophagy takes charge of long-lived proteins (Korolchuk et al., 2010). By contrast with autophagy genes that are globally over-expressed during leaf senescence, the proteasome subunit genes do not seem to be up-regulated during leaf senescence, although a very few exceptions can be found (see Roberts et al., 2012, for a review). "
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    ABSTRACT: Large numbers of publications have appeared over the last few years, dealing with the molecular details of the regulation and process of the autophagy machinery in animals, plants, and unicellular eukaryotic organisms. This strong interest is caused by the fact that the autophagic process is involved in the adaptation of organisms to their environment and to stressful conditions, thereby contributing to cell and organism survival and longevity. In plants, as in other eukaryotes, autophagy is associated with longevity as mutants display early and strong leaf senescence symptoms, however, the exact role of autophagy as a pro-survival or pro-death process is unclear. Recently, evidence that autophagy participates in nitrogen remobilization has been provided, but the duality of the role of autophagy in leaf longevity and/or nutrient recycling through cell component catabolism remains. This review aims to give an overview of leaf senescence-associated processes from the physiological point of view and to discuss relationships between nutrient recycling, proteolysis, and autophagy. The dual role of autophagy as a pro-survival or pro-death process is discussed.
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    • "In contrast, it is not fully clear if impairment of autophagy promotes proteasome activation. There are studies showing that the proteasome is not activated [176] and that at the same time accumulation and aggregation of ubiquitinated proteins occur [177] [178], whereas Wang and colleagues [179] have suggested that proteasomes are activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy-related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. Although proteasome activation has been achieved, the effect of this activation in autophagy has not been yet defined. "
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    ABSTRACT: Aging is a natural biological process that is characterized by a progressive accumulation of macromolecular damage. In the proteome, aging is accompanied by decreased protein homeostasis and function of the major cellular proteolytic systems, leading to the accumulation of unfolded, misfolded or aggregated proteins. In particular, the proteasome is responsible for the removal of normal as well as damaged or misfolded proteins. Extensive work during last several years has clearly demonstrated that proteasome activation by either genetic means or use of compounds significantly retards aging. Importantly, this represents a common feature across evolution thereby suggesting proteasome activation to be an evolutionary conserved mechanism of aging and longevity regulation. This review article reports on the means of function of these proteasome activators and how they regulate aging in different species.
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