Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids.
Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids.
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DOI：
10.4161/auto.27344
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发表时间：
2014-03
期刊：
影响因子：
13.3
通讯作者：
Mizushima N
中科院分区：
文献类型：
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作者：
Sahani MH;Itakura E;Mizushima N
SQSTM 1/p62（隔离体1）是一种多功能信号分子，参与多种细胞途径。SQSTM 1是最著名的自噬底物之一，因此被广泛用作自噬降解的指标。在这里，我们报告说，SQSTM 1的表达水平可以恢复在长期饥饿。在饥饿时，SQSTM 1最初通过自噬降解。然而，在小鼠胚胎成纤维细胞和HepG 2细胞中，SQSTM 1在长期饥饿期间恢复到基础水平，但在HeLa和HEK 293细胞中则不然。SQSTM 1的恢复依赖于其转录上调，这是由氨基酸饥饿引发的。此外，来源于自噬-溶酶体途径的氨基酸用于在饥饿条件下从头合成SQSTM 1。SQSTM 1的恢复不依赖于MTORC 1（雷帕霉素复合物1的机制靶点）的再激活。这些结果表明，饥饿细胞中SQSTM 1的表达水平至少由3个因素决定：自噬降解、转录上调和溶酶体衍生氨基酸的可用性。这项研究的结果还表明，SQSTM 1的表达水平并不总是与自噬活性呈负相关。
SQSTM1/p62 (sequestosome 1) is a multifunctional signaling molecule, involved in a variety of cellular pathways. SQSTM1 is one of the best-known autophagic substrates, and is therefore widely used as an indicator of autophagic degradation. Here we report that the expression level of SQSTM1 can be restored during prolonged starvation. Upon starvation, SQSTM1 is initially degraded by autophagy. However, SQSTM1 is restored back to basal levels during prolonged starvation in mouse embryonic fibroblasts and HepG2 cells, but not in HeLa and HEK293 cells. Restoration of SQSTM1 depends on its transcriptional upregulation, which is triggered by amino acid starvation. Furthermore, amino acids derived from the autophagy–lysosome pathway are used for de novo synthesis of SQSTM1 under starvation conditions. The restoration of SQSTM1 is independent of reactivation of MTORC1 (mechanistic target of rapamycin complex 1). These results suggest that the expression level of SQSTM1 in starved cells is determined by at least 3 factors: autophagic degradation, transcriptional upregulation, and availability of lysosomal-derived amino acids. The results of this study also indicate that the expression level of SQSTM1 does not always inversely correlate with autophagic activity.