Golgi maturation-dependent glycoenzyme recycling controls glycosphingolipid biosynthesis and cell growth via GOLPH3

Riccardo Rizzo, Domenico Russo, Kazuo Kurokawa, Pranoy Sahu, Bernadette Lombardi, Domenico Supino, Mikhail A. Zhukovsky, Anthony Vocat, Prathyush Pothukuchi, Vidya Kunnathully, Laura Capolupo, Gaelle Boncompain, Carlo Vitagliano, Federica Zito Marino, Gabriella Aquino, Daniela Montariello, Petra Henklein, Luigi Mandrich, Gerardo Botti, Henrik ClausenUlla Mandel, Toshiyuki Yamaji, Kentaro Hanada, Alfredo Budillon, Franck Perez, Seetharaman Parashuraman, Yusuf A. Hannun, Akihiko Nakano, Daniela Corda, Giovanni D’Angelo, Alberto Luini

Research output: Contribution to journalArticlepeer-review

Abstract

Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism.

Original languageEnglish
JournalEMBO Journal
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • cisternal maturation
  • Golgi
  • GOLPH3
  • mTOR
  • Trafficking

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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