c-MYC is an aggregation-prone, amyloidogenic protein

SUMMARY The transcription factor c-MYC is a central regulator of diverse biological processes and an oncogenic driver. Paradoxically, c-MYC also exhibits intrinsic tumor-suppressive activity through apoptosis, a phenomenon known as the “c-MYC paradox”. Here, we identify c-MYC as an intrinsically amyloidogenic protein. Under proteotoxic stress, c-MYC becomes detergent-insoluble aggregates. Notably, even in the absence of stress, c-MYC assembles into soluble amyloid-like oligomers in human cancer tissues and Alzheimer’s disease brains. In vitro, recombinant c-MYC proteins spontaneously form amyloid oligomers and protofibrils. In contrast, its obligate dimerization partner MAX is non-amyloidogenic and suppresses c-MYC amyloidogenesis. Mapping studies identify two short linear sequences within intrinsically disordered regions that confer amyloidogenicity. Importantly, the amyloid state of c-MYC induces apoptosis largely independently of transcription. Thus, these findings reveal a previously unrecognized amyloidogenic property of c-MYC, which contributes to its tumor-suppressing activity. Conceptually, c-MYC amyloidogenesis may serve as a built-in failsafe mechanism to restrain its oncogenic potential. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵6 Lead contact the revised version includes updated figures and main text.