PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc
Emma Lacroix, Evgenia A. Momchilova, Sahil Chandhok, Mythili Padavu, Richard Zapf, Timothy E. Audas
Abstract
In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-bodies are non-toxic, and they induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screening approach to identify candidate pathways regulating A-body biogenesis. Our data demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis meditates A-body formation during stress exposure, with AKT activation repressing glycogen synthase kinase-3 (GSK3)-mediated degradation of c-Myc. This enhances c-Myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K/AKT signaling, c-Myc, and physiological amyloid aggregates extends the range of activity for these well-established regulators while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.