Vadlamudi, R. K., Joung, I., Strominger, J. L. & Shin, J. p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J. Biol. Chem. 271, 20235-20237
p62 is a novel cellular protein which was initially identified as a phosphotyrosine-independent ligand of the SH2 domain of p56(lck). In the yeast two-hybrid system, p62 specifically interacted with ubiquitin in vivo. Furthermore, p62 bound to ubiquitin-conjugated Sepharose beads in vitro and was efficiently competed by soluble ubiquitin. The interaction was independent of ATP hydrolysis, and its dissociation did not require a reducing agent. Thus, p62 binds to ubiquitin noncovalently. Further analysis showed that the C-terminal 80 amino acids of p62 were indispensable for its interaction with ubiquitin. However, p62 has homology neither with ubiquitin C-terminal hydrolases nor with the S5a subunit of the 26 S proteasome complex, the only proteins known to bind to ubiquitin noncovalently. These results suggest that p62 belongs to a new class of ubiquitin-binding proteins and that p62 affects signal transduction at least partly through ubiquitination-mediated protein degradation.
"The UBA domain is found in many proteins involved in the degradation pathways engaging ubiquitin-like proteins, for example in Dsk2 or Rad23 involved in UPS or in p62 and NBR1 involved in autophagy-lysosomal machinery. Most UBA domains, but not all of them (Davies et al., 2004), are able to bind various ubiquitin forms, such as monoubiquitin or the K48- or K63-chains of polyubiquitin (Vadlamudi et al., 1996; Bertolaet et al., 2001a,b; Wilkinson et al., 2001; Funakoshi et al., 2002; Rao and Sastry, 2002). For instance, the UBA domain of p62 shows a preference for K63-polyubiquitinated substrates (Seibenhener et al., 2004; Long et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Tobacco Joka2 protein is a hybrid homolog of two mammalian selective autophagy cargo receptors, p62 and NBR1. These proteins can directly interact with the members of ATG8 family and the polyubiquitinated cargoes designed for degradation. Function of the selective autophagy cargo receptors relies on their ability to form protein aggregates. It has been shown that the N-terminal PB1 domain of p62 is involved in formation of aggregates, while the UBA domains of p62 and NBR1 have been associated mainly with cargo binding. Here we focus on roles of PB1 and UBA domains in localization and aggregation of Joka2 in plant cells. We show that Joka2 can homodimerize not only through its N-terminal PB1-PB1 interactions but also via interaction between N-terminal PB1 and C-terminal UBA domains. We also demonstrate that Joka2 co-localizes with recombinant ubiquitin and sequestrates it into aggregates and that C-terminal part (containing UBA domains) is sufficient for this effect. Our results indicate that Joka2 accumulates in cytoplasmic aggregates and suggest that in addition to these multimeric forms it also exists in the nucleus and cytoplasm in a monomeric form.
"The protein p62, also termed Sequestosome 1 (Sqstm1), A170, and ZIP, is a cytoplasmic endosome-associated protein known as an adaptor and scaffold for atypical protein kinase C (aPKCs) (Ishii et al., 1996; Joung et al., 1996; Puls et al., 1997; Moscat et al., 2007). p62 is a ubiquitin-binding protein (Vadlamudi et al., 1996) that facilitates the formation of inclusion bodies via its interaction with ubiquitinated proteins (Shin, 1998) and the formation of autophagosomes via its interaction with LC3/Atg8 (Komatsu et al., 2007). Recent studies showed that p62 −/− mice exhibit various abnormalities such as mature-onset neurodegeneration accompanied by accumulation of ubiquitinated tau protein in the brain at ≥6 months of age, inducing an Alzheimer-like phenotype (Ramesh Babu et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2013; 33(37):14767-14777. DOI:10.1523/JNEUROSCI.2954-12.2013 · 6.34 Impact Factor
"Noteworthy, recruitment of cytosolic p62/SQSTM1 to ubiquitinated mitochondria has been observed to promote the clustering of these mitochondria , . P62/SQSTM1 itself contains a ubiquitin-binding domain, which has been shown to bind ubiquitin , . Furthermore, it has been shown that p62/SQSTM1 self-oligomerizes  and that mutation of amino acid residues of p62/SQSTM1 important for oligomerization attenuates the clustering of mitochondria . "
[Show abstract][Hide abstract] ABSTRACT: Lipid droplets, the intracellular storage organelles for neutral lipids, exist in a wide range of sizes and of morphologically distinct organization, from loosely dispersed lipid droplets to tightly packed lipid droplet clusters. We show that the lipid droplet protein AUP1 induces cluster formation. A fraction of AUP1 is monoubiquitinated at various lysine residues. This process depends on its internal CUE domain, which is a known ubiquitin-binding domain. AUP1 with a deleted or point mutagenized CUE domain, as well as a lysine-free mutant, are not ubiquitinated and do not induce lipid droplet clustering. When such ubiquitination deficient mutants are fused to ubiquitin, clustering is restored. AUP1 mutants with defective droplet targeting fail to induce clustering. Also, another lipid droplet protein, NSDHL, with a fused ubiquitin does not induce clustering. The data indicate that monoubiquitinated AUP1 on the lipid droplet surface specifically induces clustering, and suggest a homophilic interaction with a second AUP1 molecule or a heterophilic interaction with another ubiquitin-binding protein.
PLoS ONE 09/2013; 8(9):e72453. DOI:10.1371/journal.pone.0072453 · 3.23 Impact Factor
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