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J Cell Sci. 2019 Jul 22. pii: jcs.231886. doi: 10.1242/jcs.231886. [Epub ahead of print]

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

Author information

1
Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, OH 45435, USA.
2
Human Signatures Branch, Human-Centered ISR Division, Airman Systems Directorate, 711 Human Performance Wing, Air Force Research Laboratory, Wright Patterson Air Force Base, OH 45433, USA.
3
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
4
Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, OH 45435, USA kwang-jin.cho@wright.edu.

Abstract

Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of posttranslational modifications, H- 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 is one of the three proteins that compose subunit c of the F0 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 (PI) 4-phosphate (P) 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.

KEYWORDS:

Golgi; K-Ras; Mitochondria; Phosphatidylinositol 4-kinase; Phosphatidylinositol 4-phosphate; Phosphatidylserine

PMID:
31331963
DOI:
10.1242/jcs.231886

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