Abstract
mTORC1 and AMPK are mutually antagonistic sensors of nutrient and energy status that have been implicated in many human diseases including cancer, Alzheimer’s disease, obesity and type 2 diabetes. Starved cells of the social amoeba Dictyostelium discoideum aggregate and eventually form fruiting bodies consisting of stalk cells and spores. We focus on how this bifurcation of cell fate is achieved. During growth mTORC1 is highly active and AMPK relatively inactive. Upon starvation, AMPK is activated and mTORC1 inhibited; cell division is arrested and autophagy induced. After aggregation, a minority of the cells (prestalk cells) continue to express much the same set of developmental genes as during aggregation, but the majority (prespore cells) switch to the prespore program. We describe evidence suggesting that overexpressing AMPK increases the proportion of prestalk cells, as does inhibiting mTORC1. Furthermore, stimulating the acidification of intracellular acidic compartments likewise increases the proportion of prestalk cells, while inhibiting acidification favors the spore pathway. We conclude that the choice between the prestalk and the prespore pathways of cell differentiation may depend on the relative strength of the activities of AMPK and mTORC1, and that these may be controlled by the acidity of intracellular acidic compartments/lysosomes (pHv), cells with low pHv compartments having high AMPK activity/low mTORC1 activity, and those with high pHv compartments having high mTORC1/low AMPK activity. Increased insight into the regulation and downstream consequences of this switch should increase our understanding of its potential role in human diseases, and indicate possible therapeutic interventions.
Highlights
Individual starved amoebae of D. discoideum aggregate to form loose mounds, which are transformed into “tight aggregates”, in which the amoebae are closely associated via lateral and polar contacts and become surrounded by a complex extracellular matrix of protein and cellulose to create, in effect, a multicellular organism (Kessin, 2001; Pears and Gross, 2021)
If we accept that the prespore pathway is initiated when AMPK is downregulated, and mTORC1 upregulated, in some 80% of the aggregated cells, what might be responsible for this switch? During growth and early in development, the acidic intracellular compartments of amoebae [ these are of various kinds, we will refer to them throughout as acidic vesicles (AVs)] are highly acidic and are stained by the weak base, neutral red, whereas at the first finger and slug stage of development, the AVs of prespore cells have lost their acidity and are unstained (Bonner, 1952). We suggest that this change in acidic vesicle pH is responsible for downregulating AMPK and upregulating mTORC1 in these cells, we cannot exclude the possibility that it is a consequence of their differences in gene expression
We suggest that defects in vesical acidification have two, probably independent, consequences: on the one hand they result in activation of the DhkC phosphorelay and breakdown of cyclic AMP (cAMP), on the other they inhibit AMPK activation
Summary
Individual starved amoebae of D. discoideum aggregate to form loose mounds, which are transformed into “tight aggregates”, in which the amoebae are closely associated via lateral and polar contacts and become surrounded by a complex extracellular matrix of protein and cellulose to create, in effect, a multicellular organism (Kessin, 2001; Pears and Gross, 2021). It has already been proposed that the mutual inhibition between mTORC1 and AMPK constitutes a regulatory switch responsible for initiating development (Jaiswal and Kimmel, 2019), and our suggestion is just an extension of this idea to account for the bifurcation of cell fates.
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