p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate

Proteolytic systems and the aggresome pathway contribute to preventing accumulation of cytotoxic aggregation-prone proteins. Although polyubiquitylation is usually required for degradation or aggresome formation, several substrates are processed independently of ubiquitin through a poorly understood...

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Veröffentlicht in:Journal of cell science 2011-08, Vol.124 (Pt 16), p.2692-2701
Hauptverfasser: Watanabe, Yoshihisa, Tanaka, Masaki
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container_title Journal of cell science
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creator Watanabe, Yoshihisa
Tanaka, Masaki
description Proteolytic systems and the aggresome pathway contribute to preventing accumulation of cytotoxic aggregation-prone proteins. Although polyubiquitylation is usually required for degradation or aggresome formation, several substrates are processed independently of ubiquitin through a poorly understood mechanism. Here, we found that p62/SQSTM1, a multifunctional adaptor protein, was involved in the selective autophagic clearance of a non-ubiquitylated substrate, namely an aggregation-prone isoform of STAT5A (STAT5A_ΔE18). By using a cell line that stably expressed STAT5A_ΔE18, we investigated the properties of its aggregation and degradation. We found that STAT5A_ΔE18 formed non-ubiquitylated aggresomes and/or aggregates by impairment of proteasome functioning or autophagy. Transport of these aggregates to the perinuclear region was inhibited by trichostatin A or tubacin, inhibitors of histone deacetylase (HDAC), indicating that the non-ubiquitylated aggregates of STAT5A_ΔE18 were sequestered into aggresomes in an HDAC6-dependent manner. Moreover, p62 was bound to STAT5A_ΔE18 through its PB1 domain, and the oligomerization of p62 was required for this interaction. In p62-knockdown experiments, we found that p62 was required for autophagic clearance of STAT5A_ΔE18 but not for its aggregate formation, suggesting that the binding of p62 to non-ubiquitylated substrates might trigger their autophagic clearance.
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subjects Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Anilides - pharmacology
Autophagy - genetics
Gene Knockdown Techniques
HeLa Cells
Histone Deacetylase 6
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - metabolism
Humans
Hydroxamic Acids - pharmacology
Mutation - genetics
Protein Binding
Protein Multimerization - genetics
Protein Transport - drug effects
Proteolysis
Sequestosome-1 Protein
STAT5 Transcription Factor - genetics
STAT5 Transcription Factor - metabolism
Transgenes - genetics
Ubiquitination
title p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate
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