Abstract

Macroautophagy (hereafter, autophagy) is a multi‐step process through which cells degrade damaged or unutilized proteins or organelles (cargos) to maintain homeostasis. In the final step of autophagy, cargos are degraded by lysosomal enzymes, whose activities require an acidic environment. Intracellular Ca2+ has been shown to play diverse roles in autophagy. In many cases, Ca2+ signals are transduced into cellular activities by forming a complex with the ubiquitous Ca2+‐binding protein calmodulin (CaM), which then activates numerous target proteins, estimated to be over 300. However, CaM is not expressed sufficiently for all these targets. This generates a limiting condition in which CaM availability is competed for. Although several CaM‐binding proteins have been implicated in autophagy, the role of CaM availability in autophagy is unknown, especially in basal condition when there are no stimulated increases in intracellular Ca2+. Here we show that overexpressing CaM promotes autophagic flux in basal, unstimulated condition. Removal of amino acids triggers acute intracellular Ca2+ signals, and autophagic flux during this time frame is also significantly higher in CaM‐overexpressing cells compared to the wildtype counterparts. Inhibiting CaM using various CaM antagonists is associated with increases in lysosomal pH and accumulation of LC3‐II. Finally, buffering cellular free CaM using a high‐affinity CaM‐binding protein that can bind CaM at resting Ca2+ levels significantly increases basal lysosomal pH. These data indicate that CaM availability aids in maintaining optimal lysosomal pH, which contributes to the regulation of basal autophagy.

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