Substrate recognition in selective autophagy and the ubiquitin–proteasome system

Abstract

Dynamic protein turnover through regulated protein synthesis and degradation ensures cellular growth, proliferation, differentiation and adaptation. Eukaryotic cells utilize two mechanistically distinct but largely complementary systems - the 26S proteasome and the lysosome (or vacuole in yeast and plants) - to effectively target a wide range of proteins for degradation. The concerted action of the ubiquitination machinery and the 26S proteasome ensures the targeted and tightly regulated degradation of a subset of commonly short-lived cellular proteins. Autophagy is a distinct degradation pathway, which transports a highly heterogeneous set of cargos in dedicated vesicles, called autophagosomes, to the lysosome. There the cargo becomes degraded and its molecular building blocks are recycled. While general autophagy randomly engulfs portions of the cytosol, selective autophagy employs dedicated cargo adaptors to specifically enrich the forming autophagosomes for a certain type of cargo as a response to various intra- or extracellular signals. Selective autophagy targets a wide range of cargos including long-lived proteins and protein complexes, organelles, protein aggregates and even intracellular microbes. In this review we summarize available data on cargo recognition mechanisms operating in selective autophagy and the ubiquitin-proteasome system (UPS), and emphasize their differences and common themes. Moreover, we derive general regulatory principles underlying cargo recognition in selective autophagy, and describe the system-wide crosstalk between these two cellular protein degradation systems. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Autophagy at the crossroads of catabolism and anabolism

“…However, notably, a recent study in S. cerevisiae reported that the degradation of ER is topologically equivalent to microautophagy but is not dependent on any genetic components of the core autophagy machinery or microautophagy machinery 40 . Selective autophagy can also target large macromolecules, such as lipids and iron complexes (see below), as well as intracellular pathogens (via a process termed xenophagy) and transient macromolecular structures within cells, such as the inflammasome, midbody and midbody ring [41][42][43][44] .…”

ArabidopsisATG8-INTERACTING PROTEIN1 Is Involved in Autophagy-Dependent Vesicular Trafficking of Plastid Proteins to the Vacuole

“…Starvationinduced autophagy is classically associated with bulk turnover of macromolecules and organelles in the vacuole upon exposure to stresses causing extensive energy deprivation (Han et al, 2011;Hayward and Dinesh-Kumar, 2011;Li and Vierstra, 2012;Yoshimoto, 2012). In addition, autophagy targets specific proteins, protein aggregates, or organelles for recycling in the vacuole by a process called selective autophagy (Floyd et al, 2012;Li and Vierstra, 2012;Schreiber and Peter, 2014).…”

Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

“…However, recent findings suggest that this post-translational modification plays an important role in the selective autophagic degradation of several proteins and serves as a recognition signal for cargo recruitment (23)(24)(25)(26). At the molecular level, the polyubiquitin moieties are recognized by the proteins adaptors (i.e.…”

“…However, in the last few years, converging evidence demonstrated that this degradation route is also selective, and emphasis was made on the role of the ubiquitin system in this selectivity (23)(24)(25)(26). To verify whether ubiquitination is required for PLK2-mediated ␣-syn autophagic turnover and may confer selectivity to this process, we treated HEK-239T cells overexpressing ␣-syn and PLK2 with [4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) (12.5 M), a potent and irreversible inhibitor of E1 ubiquitin ligase (27)(28)(29)(30).…”