Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A et al.. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603-614

Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway.
The Journal of Cell Biology (Impact Factor: 9.83). 12/2005; 171(4):603-14. DOI: 10.1083/jcb.200507002
Source: PubMed


Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and co-immunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

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    • " in the LC3 lipidation reaction ( Hanada et al . , 2007 ) . In addition to components directly involved in the autophagic process , markers of autophagic activity have also been identified . Sequestosome 1 ( p62 / SQSTM1 ) binds to Atg8 / LC3 and disruptions in autophagy have been found to be associated with higher p62 / SQSTM1 expression levels ( Bjorkoy et al . , 2005 ; Wang et al . , 2006 ; Komatsu et al . , 2007b ; Pankiv et al . , 2007 ) , while higher lysosomal - associated membrane protein 1 ( LAMP1 ) can indicate the presence of more lysosomes and autophagosomes during rises in autophagic activity ( Klionsky et al . , 2008 ) . While cellular differences resulting from prolonged HIV infection can"
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    Frontiers in Microbiology 07/2015; 6:653. DOI:10.3389/fmicb.2015.00653 · 3.99 Impact Factor
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    • "At the current state of research, it is also possible to envision that at low concentrations poly-ubiquitin chains actively crosslink p62 filaments (Morimoto et al., 2015), whereas at molar excess poly-ubiquitin chains disassemble p62 filaments. Moreover , membrane-enwrapped p62 bodies can also enter the autophagosomal pathway without enclosing additional cytoplasmic material to be degraded (Bjørkøy et al., 2005). Thus, p62 bodies will have a cytoprotective function to target misfolded cytotoxic proteins for degradation, as p62 sequesters them and prevents their interference with basic cellular functions. "
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    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.062 · 8.36 Impact Factor
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    • "This activity relies on receptors that bind to cargo and Atg8 (LC3) present at autophagosomal membranes via LC3-interacting regions (LIR) [76], causing engulfment of bound substrates by the autophagic membrane. In mammalian cells, the receptors p62 and Nbr1 target ubiquitinated protein inclusions (ALIS/DALIS) [77] and aggregates of polyQ-proteins [78] for a specific form of selective autophagy, termed aggrephagy [79]. In yeast, the adaptor protein Cue5 has recently been identified by Jentsch and coworkers [75], that is A C C E P T E D M A N U S C R I P T "
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