Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates

By Viktor I. Korolchuk, A. Mansilla, Fiona M Menzies, D. Rubinsztein. Molecules and Cells, 2009

674 citations recorded by the source corpus.

Summary The two main routes that cells use for degrading intracellular proteins are the ubiquitin-proteasome and autophagy-lysosome pathways, which have been thought to have largely distinct clients. Here, we show that autophagy inhibition increases levels of proteasome substrates. This is largely due to p62 (also called A170/SQSTM1) accumulation after autophagy inhibition. Excess p62 inhibits the clearance of ubiquitinated proteins destined for proteasomal degradation by delaying their delivery to the proteasome's proteases. Our data show that autophagy inhibition, which was previously believed to only affect long-lived proteins, will also compromise the ubiquitin-proteasome system. This will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences.

Subfields: Epidemiology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/a412dc5ea91f6e467f18dc35a6b7e6cd2b714119

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Citations in the corpus

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 (2010, background): “It has been reported that p62 accumulation in growing cell lines leads to a decrease in the ubiquitin–proteasomal (UPS) flu”
Autophagy and aging. (2011, background): “Thus, at the cellular level, insufficient autophagy compromises the degradation of ubiquitin-proteasome pathway substrates due to the accumulation of p62/SQSTM, resulting in higher levels of short-lived regulatory proteins like p53 (Korolchuk et al., 2009), which in turn can inhibit autophagy (Tasde”
Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity (2012, background): “The disruption in clearance of polyubiquitinated proteins upon autophagy dysfunction is further evidence that autophagy, in addition to the proteasome, is involved in degradation of ubiquitin-targeted proteins [118].”
Autophagy as a target for anticancer therapy (2011, background): “In terms of protein degradation, autophagy is complementary to the ubiquitin–proteasome system”
Selective autophagy: ubiquitin-mediated recognition and beyond (2010, background): “In contrast, long-term inhibition of autophagy has been shown to slow the degradation of short-lived UPS substrate”
Ubiquitination and selective autophagy (2012, background): “Moreover, long-term inhibition of autophagy can increases proteasomal substrates level by compromising the UPS as a consequence of p62 accumulation.(25) Finally, chaperones and co-chaperones such”
Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy (2011, positive): “Our results provide evidence for the concept that the two major degradative pathways—the UPS and autophagy—are functionally linked (37).”
Autophagy: Renovation of Cells and Tissues (2011, background): “, 2006) and impair the degradation of substrates destined for the proteasome (Korolchuk et al., 2009).”
FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis During Aging (2010, background): “In agreement with this notion, suppression of basal autophagy leads to the accumulation of polyubiquitin protein aggregates in a number of contexts (Korolchuk et al., 2009; Rubinsztein, 2006).”
Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. (2011, background): “…has been implicated as a compensatory pathway for proteasomal protein degradation (Bjørkøy et al., 2005; Kirkin et al., 2009; Komatsu et al., 2007; Korolchuk et al., 2009), as autophagy can remove protein aggregates (Bjørkøy et al., 2005; Filimonenko et al., 2010; Iwata et al., 2005;…”
p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation (2016, positive): “While proteasome deficiency enhances autophagy, autophagy inactivation compromises the ubiquitin–proteasome system due to surplus p62, which delays proteasomal substrate delivery to the proteasome with no changes shown in proteasomal catalytic activity [2].”
PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “In contrast, impairment of autophagy prevents ubiquitinated protein delivery to the proteasome for degradation (29).”
A role for ubiquitin in selective autophagy. (2009, background): “Inhibition of autophagy and accumulation of p62 slowed down degradation of regular (short-lived) proteasomal substrates, most likely due to the excessive interaction between stabilized oligomeric p62 and K48 Ub-conjugated substrates (Korolchuk et al., 2009).”