期刊
JOURNAL OF CELL SCIENCE
卷 124, 期 16, 页码 2692-2701出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.081232
关键词
Non-ubiquitylated substrate; Aggresome; HDAC6; p62/SQSTM1; Autophagy
类别
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_Delta E18). By using a cell line that stably expressed STAT5A_Delta E18, we investigated the properties of its aggregation and degradation. We found that STAT5A_Delta E18 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_Delta E18 were sequestered into aggresomes in an HDAC6-dependent manner. Moreover, p62 was bound to STAT5A_Delta E18 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_Delta E18 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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