Structural Basis for Sorting Mechanism of p62 in Selective Autophagy*

By Yoshinobu Ichimura, Taichi Kumanomidou, Yu-shin Sou, T. Mizushima, J. Ezaki, T. Ueno, E. Kominami, T. Yamane, Keiji Tanaka, M. Komatsu. Journal of Biological Chemistry, 2008

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Impairment of autophagic degradation of the ubiquitin- and LC3-binding protein “p62” leads to the formation of cytoplasmic inclusion bodies. However, little is known about the sorting mechanism of p62 to autophagic degradation. Here we identified a motif of murine p62 consisting of 11 amino acids (Ser334-Ser344) containing conserved acidic and hydrophobic residues across species, as an LC3 recognition sequence (LRS). The crystal structure of the LC3-LRS complex at 1.56Å resolution revealed interaction of Trp340 and Leu343 of p62 with different hydrophobic pockets on the ubiquitin fold of LC3. In vivo analyses demonstrated that p62 mutants lacking LC3 binding ability accumulated without entrapping into autophagosomes in the cytoplasm and subsequently formed ubiquitin-positive inclusion bodies as in autophagy-deficient cells. These results demonstrate that the intracellular level of p62 is tightly regulated by autophagy through the direct interaction of LC3 with p62 and reveal that selective turnover of p62 via autophagy controls inclusion body formation.

Subfields: Epidemiology, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/35145bb1648360bcd497256c99d185ca87c08d94

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Citations in the corpus

Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. (2011, background): “…balance is shifted to phosphorylated state when the polyUb protein level is increased and the polyUb bound S403-phos-p62 is efficiently sequestered in the sequestosome, followed by engulfment in the autophagosome through p62-LC3 interaction (Pankiv et al., 2007, Ichimura et al., 2008).”
p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation (2016, neutral): “accumulation in autophagy-null cells [30].”
Nrf2, the Master Regulator of Anti-Oxidative Responses (2017, background): “Autophagy can be non-selective, especially induced by starvation, but there is also a basal autophagy that selectively sorts proteins and unwanted organelles to maintain cellular omeostasis [20].”
p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both (2010, background): “6A).(12,24,25) To assess whether a similar mechanism is responsible for Parkin-induced aggregation of depolarized mitochondria, we tested the ability of wild-type and mutants of p62 to rescue the mitochondrial aggregation defect in p62 /- MEFs.”
Mechanisms of Selective Autophagy (2016, positive): “Cargo receptors bind to ATG8-family proteins via a conserved LC3-Interacting Region (LIR) motif, also known as Atg8-Interacting Motif (AIM) [46,81].”
Deacetylation of nuclear LC3 drives autophagy initiation under starvation. (2015, background): “Nevertheless, because glutamine is more hydrophobic than lysine, the finding that lysine-to-glutamine replacement prevents the LC3-Atg7 interaction suggests a crucial role of the ionic interactions between the acidic residues in the C-terminal region of Atg7 and the basic residues of LC3, including ”
A role for ubiquitin in selective autophagy. (2009, background): “These protein aggregates also depend on the functional PB1 domain of p62, which underscores the relevance of the p62 oligomerization potential (Ichimura et al., 2008; Pankiv et al., 2007). p62 is an LC3 interaction partner in vivo (Komatsu et al., 2007; Pankiv et al., 2007) and is constantly…”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, methodology): “The turnover of specific proteins can also be measured in a pulse-chase regimen using the Tet-ON/OFF system and subsequent western blot analysis.(474,475) In this type of assay a considerable fraction of the measured degradation will be non-autophagic, and thus it is important to also measure, in pa”
Dynamics and diversity in autophagy mechanisms: lessons from yeast (2009, background): “Interestingly, recent structural studies revealed a common interaction between these receptors and Atg8 homologues: the Trp-X-X-Leu motif in the receptors binds to the highly conserved, hydrophobic pocket in the Atg8 homologues in a similar manne”
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells (2011, background): “p62 is a ubiquitously expressed cellular protein that is conserved in metazoa but not in plants and fungi, and recently it has been known as one of the selective substrates for autophagy (Bjørkøy et al., 2005; Pankiv et al., 2007; Ichimura et al., 2008).”
Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. (2014, background): “Its core motif conforms to the formula Q-X-X-G—where Q is an aromatic amino acid (W/F/Y), G is hydrophobic (L/I/V), and X can be any amino acid—the so-called canonical LIR (Ichimura et al., 2008; Pankiv et al., 2007).”
The LIR motif – crucial for selective autophagy (2013, background): “The structures of p62 and Atg19 peptides bound to LC3B and Atg8, respectively, revealed a common W-x-x-L motif (x5any amino acid) (Ichimura et al., 2008b; Noda et al., 2008) (Fig.”