Figure 1.

A MCOLN1-PPP3/calcineurin-TFEB-SQSTM1/p62 feed-forward loop activates autophagy following proteasome impairment. Proteasome malfunction promotes dephosphorylation and nuclear translocation of TFEB through stabilizing and activating PPP3/calcineurin and suppressing MTOR signaling. Activated TFEB induces the expression of genes required for autophagy and lysosome biogenesis, including those encoding MCOLN1 and SQSTM1. MCOLN1 in turn mediates lysosomal calcium release to further promote PPP3/calcineurin activation, whereas SQSTM1 appears to suppress MTOR, thereby leading to a persistent activation of TFEB and autophagy. Meanwhile, the upregulated SQSTM1 also promotes aggregation of ubiquitinated proteins and is required for targeting at least a subset of ubiquitinated proteins for autophagic degradation to compensate for proteasome malfunction. Adopted from Pan [1] with permission