Journal
AUTOPHAGY
Volume 16, Issue 11, Pages 2114-2116Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1816666
Keywords
macroautophagy; PPP3/calcineurin; PSMC2; SQSTM1/p62; TFEB
Categories
Funding
- American Heart Association [AHA00182]
- National Heart, Lung, and Blood Institute [HL085629, HL072166, HL131667, HL153614, HL124248]
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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 asMcoln1andSqstm1. 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.
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