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Calmodulin availability regulates basal autophagy
Elizabeth McConnaha, MS, PhD’25, Jennifer Giles, MA, Eric Wauson, PhD, and Quang-Kim Tran, MD, PhD
Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA
Autophagy is a process by which cells degrade damaged or unutilized proteins or organelles to maintain homeostasis. In the final step of autophagy, cells utilize lysosomal degradative enzymes to breakdown unwanted macromolecules. To maintain lysosomal enzyme functions, an acidic lysosomal pH must be conserved. In autophagy, intracellular calcium has been shown to play important roles. Calmodulin (CaM) is the key transducer of intracellular calcium signaling by binding with a large network of CaM-binding proteins. However, calmodulin is not expressed sufficiently for its target proteins, generating a limiting condition in which calmodulin availability is competed for and as such regulates cell functions. Although several CaM-binding proteins have been implicated in autophagy, there is no investigation on the correlation between CaM availability and the regulation of autophagy, especially in basal condition when there are no stimulated increases in intracellular calcium. Here we show how CaM availability plays a role in the regulation of basal autophagy. In C1293 cells, a monoclonal stable cell line that overexpresses CaM, autophagic flux was significantly increased at the basal state when compared to the wildtype counterpart HEK293 cells. During amino acid starvation, the C1293 cells maintained the elevated autophagic flux. By inhibiting CaM with various CaM antagonists or buffering CaM using a very high-affinity CaM binding protein, we show decreased CaM availability alkalinizes basal lysosomal pH. This pH change was demonstrated using LysoTracker Green or LysoSensor Yellow/Blue. Taken together, CaM availability aids in maintaining a functional lysosome, which contributes to the regulation of basal autophagy.