Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

Abstract

The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signaling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction. Thus, the lysosome reveals itself as a hub for the signaling pathways that regulate cellular homeostasis.

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

“…Recently, transcription factor EB (TFEB) was discovered as a master regulator of lysosomal and autophagic function (Settembre et al ., 2011), and its nuclear distribution following mTOR inactivation is an accepted mechanistic explanation for the activation of autophagy (Roczniak‐Ferguson et al ., 2012; Medina et al ., 2015). According to this mTOR‐TFEB axis theory, mTOR inactivation‐induced TFEB dephosphorylation leads to TFEB translocation to the nucleus, which activates the transcription of specific lysosomal genes (Settembre et al ., 2011).…”

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy

“…However, since lysosomal ASM-generated ceramides are spatially constrained within lysosomes, they may contribute to lysosomal membrane biophysical properties, such as stiffness. These membrane perturbations may affect docking and signaling by interfering with the insertion of farnesylated and consistent affected sphingolipid following ASM inhibition, it is likely that the decreased sphingosine content in the lysosome may have significantly altered the lysosomal calcium efflux, ultimately affecting TFEB phosphorylation through calcineurin (21). Alternatively, subsequent reductions in S1P levels may be implicated, although increased rather than decreased intracellular S1P have been associated with triggering autophagy (22).…”

Multistep regulation of TFEB by MTORC1

“…6 TFEB is also implicated in other functions like autophagy, 7 endocytosis, 8 exocytosis, 9 lipid metabolism, 10 the antiviral response, 11 and lysosomal calcium signaling. 12 Mice deficient for Tfeb/Tcfeb die at midgestation due to deficient placental vascularization 13 and may exhibit defects in endoderm development.…”