p62 Coordinates Autophagy, cAMP Signalling, and Cell-Fate Determination in Dictyostelium discoideum

p62/SQSTM1 is a multifunctional adaptor protein playing a central role in the regulation of autophagy and stress response pathways in higher eukaryotes. However, its functional relevance in lower eukaryotes like Dictyostelium remains largely unexplored. In this study, we demonstrate that Dictyostelium p62 is crucial for cAMP-mediated development and autophagy. Loss of p62 alters levels of intracellular glucose, cAMP, ubiquitinated proteins and autophagic flux. These defects result in impaired cell aggregation and abnormal fruiting body formation, accompanied by reduced spore viability. Interestingly, pulsing of p62 null cells with exogenous cAMP could partially rescue the developmental defects, implicating a role of p62 in maintaining the intracellular cAMP levels required for starvation stress-induced development. p62 also influences cell-fate decisions during development as its deletion biases cells toward pre-spore differentiation, whereas overexpression promotes pre-stalk lineage. Mechanistically, p62 also modulates autophagy flux potentially via regulating AMPK levels along with cAMP dynamics. Together, these findings position p62 as an evolutionarily conserved key adaptor protein that provides new insights into the molecular mechanisms underlying multicellular development.