Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria

J Cell Sci. 2019 Aug 22;132(16):jcs231886. doi: 10.1242/jcs.231886.

Abstract

Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of post-translational modifications, H-Ras and N-Ras traffic to the PM from the Golgi via the classical exocytic pathway, but the exact mechanism of K-Ras trafficking to the PM from the ER is not fully characterized. ATP5G1 (also known as ATP5MC1) is one of the three proteins that comprise subunit c of the F 0 complex of the mitochondrial ATP synthase. In this study, we show that overexpression of the mitochondrial targeting sequence of ATP5G1 perturbs glucose metabolism, inhibits oncogenic K-Ras signaling, and redistributes phosphatidylserine (PtdSer) to mitochondria and other endomembranes, resulting in K-Ras translocation to mitochondria. Also, it depletes phosphatidylinositol 4-phosphate (PI4P) at the Golgi. Glucose supplementation restores PtdSer and K-Ras PM localization and PI4P at the Golgi. We further show that inhibition of the Golgi-localized PI4-kinases (PI4Ks) translocates K-Ras, and PtdSer to mitochondria and endomembranes, respectively. We conclude that PI4P at the Golgi regulates the PM localization of PtdSer and K-Ras.This article has an associated First Person interview with the first author of the paper.

Keywords: Golgi; K-Ras; Mitochondria; Phosphatidylinositol 4-kinase; Phosphatidylinositol 4-phosphate; Phosphatidylserine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cricetinae
  • Dogs
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism*
  • HEK293 Cells
  • Humans
  • Madin Darby Canine Kidney Cells
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Transport / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*

Substances

  • KRAS protein, human
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 4-phosphate
  • Mitochondrial Proton-Translocating ATPases
  • Proto-Oncogene Proteins p21(ras)