蛋白酶体功能障碍激活 PPP3/calcineurin-TFEB-SQSTM1/p62 通路诱导心脏发生巨自噬。
Proteasome malfunction activates the PPP3/calcineurin-TFEB-SQSTM1/p62 pathway to induce macroautophagy in the heart.
机构信息
Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University , Augusta, GA, USA.
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota , Vermillion, SD, USA.
出版信息
Autophagy. 2020 Nov;16(11):2114-2116. doi: 10.1080/15548627.2020.1816666. Epub 2020 Sep 22.
Proteasome inhibition (PSMI) is known to activate macroautophagy (autophagy hereafter), but the underlying mechanisms remain to be fully delineated. Here we discuss our recent work identifying an important PPP3/calcineurin-TFEB-SQSTM1/p62 pathway in mediating activation of autophagy by PSMI, a compensatory process for the heart with proteasome malfunction. Through increasing PPP3/calcineurin activity and inhibiting MTOR signaling, PSMI promotes the dephosphorylation and thereby nuclear translocation of TFEB, resulting in transactivation of genes in the autophagic-lysosomal pathway (ALP) such as and . We have discovered that SQSTM1 is required for not only induction of autophagy but also cardiac activation of TFEB by PSMI, unveiling a novel feedforward role for SQSTM1 in TFEB activation.
蛋白酶体抑制（PSMI）已知可激活巨自噬（下文简称自噬），但其潜在机制仍有待充分阐明。在这里，我们讨论了我们最近的工作，确定了一个重要的 PPP3/钙调神经磷酸酶-TFEB-SQSTM1/p62 途径，该途径介导 PSMI 诱导的自噬，这是蛋白酶体功能障碍的心脏的一种代偿过程。通过增加 PPP3/钙调神经磷酸酶的活性和抑制 MTOR 信号，PSMI 促进 TFEB 的去磷酸化，从而使其转位到细胞核，导致自噬溶酶体途径（ALP）中的基因转录激活，如 和 。我们发现 SQSTM1 不仅是自噬的诱导所必需的，也是 PSMI 诱导 TFEB 激活的必需条件，揭示了 SQSTM1 在 TFEB 激活中的新的正反馈作用。
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