PI3K/AKT Signaling Mediates Stress-Inducible Amyloid Aggregation Through c-myc
Lacroix, E.; Momchilova, E. A.; Chandhok, S.; Padavu, M.; Zapf, R.; Audas, T. E.
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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-body are non-toxic, and 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 screen to identify candidate pathways regulating A-body biogenesis. Our data demonstrates that the PI3K signaling axis meditates A-body formation during heat shock, by activating AKT and repressing 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 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.
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