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

• Published in: Journal of cell science Vol. 132; no. 16
• Main Authors: Miller, Taylor E, Henkels, Karen M, Huddleston, Mary, Salisbury, Richard, Hussain, Saber M, Sasaki, Atsuo T, Cho, Kwang-Jin
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 22.08.2019
• Subjects: Mitochondria; Golgi; Phosphatidylinositol 4-kinase; K-Ras; Phosphatidylserine; Phosphatidylinositol 4-phosphate
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.231886

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 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.