RIP1 negatively regulates basal autophagic flux through TFEB to control sensitivity to apoptosis

Tohru Yonekawa, Graciela Gamez, Jihye Kim, Aik Choon Tan, Jackie Thorburn, Jacob Gump, Andrew Thorburn, Michael J. Morgan

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

In a synthetic lethality/viability screen, we identified the serine-threonine kinase RIP1 (RIPK1) as a gene whose knockdown is highly selected against during growth in normal media, in which autophagy is not critical, but selected for in conditions that increase reliance on basal autophagy. RIP1 represses basal autophagy in part due to its ability to regulate the TFEB transcription factor, which controls the expression of autophagy-related and lysosomal genes. RIP1 activates ERK, which negatively regulates TFEB though phosphorylation of serine 142. Thus, in addition to other pro-death functions, RIP1 regulates cellular sensitivity to pro-death stimuli by modulating basal autophagy. Synopsis This study shows that RIP1 identified in a kinome screen for modulators of survival when cells depend on autophagy inhibits basal autophagy through the ERK/TFEB pathway, thereby modulating sensitivity to apoptotic stimuli. Expression of RIP1 shRNA is selected against under normal growth conditions, but is selected for when ATG12 is knocked down, or when cells are starved in EBSS. Acute depletion of RIP1 in many cell types leads to increases in basal autophagy. This increase in autophagy is associated with decreased basal ERK activity and TFEB phosphorylation, and increased transcriptional activity of TFEB. Increases in basal autophagy associated with RIP1 depletion affect the overall responses of cells to death receptor stimuli in a context-specific manner. This study shows that RIP1 identified in a kinome screen for modulators of survival when cells depend on autophagy inhibits basal autophagy through the ERK/TFEB pathway, thereby modulating sensitivity to apoptotic stimuli.

Original languageEnglish
Pages (from-to)700-708
Number of pages9
JournalEMBO Reports
Volume16
Issue number6
DOIs
Publication statusPublished - 2015 Jun 1

Keywords

  • ERK
  • RIP1 (RIPK1)
  • TFEB
  • autophagy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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