ABSTRACT

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 Mcoln1 and Sqstm1. 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.

摘要

已知蛋白酶体抑制 (PSMI) 可激活巨自噬（以下称为自噬），但其潜在机制仍有待完全阐明。在这里，我们讨论了我们最近的工作，确定了重要的 PPP3/钙调神经磷酸酶-TFEB-SQSTM1/p62 通路在介导 PSMI 激活自噬中，这是一种蛋白酶体功能障碍心脏的代偿过程。通过增加 PPP3/钙调神经磷酸酶活性和抑制 MTOR 信号，PSMI 促进 TFEB 的去磷酸化，从而促进 TFEB 的核易位，导致自噬 - 溶酶体途径 (ALP) 中的基因如Mcoln1和Sqstm1 的反式激活. 我们发现 SQSTM1 不仅需要 PSMI 诱导自噬，还需要 PSMI 心脏激活 TFEB，揭示了 SQSTM1 在 TFEB 激活中的新前馈作用。