PURPL directly modulates ULK1 phosphorylation to inhibit autophagic cell death

Abstract

Autophagic cell death is characterized by uncontrolled macroautophagy/autophagy overactivation. Yet, the key modulators involved in autophagic cell death remain underexplored. In this study, PURPL (p53 upregulated regulator of p53 levels) is identified to act as an oncogene in promoting cell proliferation, colony formation, migration, invasiveness and suppressing cell death in melanoma cells. Further in vitro and in vivo investigations confirmed PURPL executes anti-autophagic roles in melanoma and the cell death repressed by PURPL is autophagic cell death. RNA affinity isolation followed by HPLC-MS showed PURPL physically interacts with MTOR and ULK1. PURPL inhibits autophagy by promoting the formation of mTOR-mediated anti-autophagic p-ULK1 (Ser757) and repressing AMPK-mediated pro-autophagic p-ULK1 (Ser555 or Ser317). Our findings demonstrate that PURPL interacts with MTOR to modulate the activity of autophagy initiation factor ULK1 for inhibiting autophagic cell death in melanoma and may present a potential intervention target for melanoma therapy.

Keywords

• autophagic cell death
• melanoma
• mtor
• purpl
• ulk1