A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival

Abstract

The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. Here, we report that serine pyrophosphorylation - an enigmatic posttranslational modification triggered by inositol pyrophosphate signaling molecules - controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Pyrophosphorylation of MYC promotes its interaction with the E3 ubiquitin ligase FBW7, thereby enhancing MYC polyubiquitination and degradation. FBW7 can bind directly to the PEST domain of MYC in a pyrophosphorylation-dependent manner. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells, and promotes cell proliferation in response to mitogens. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.