The oncoprotein GOLPH3 (Golgi phosphoprotein 3) is an evolutionarily conserved phosphatidylinositol 4-phosphate effector, mainly localized to the Golgi apparatus, where it supports organelle architecture and vesicular trafficking. Overexpression of human GOLPH3 correlates with poor prognosis in several cancer types and is associated with enhanced signaling downstream of mTOR (mechanistic target of rapamycin). However, the molecular link between GOLPH3 and mTOR remains elusive. Studies in Drosophila melanogaster have shown that Translationally controlled tumor protein (Tctp) and 14-3-3 proteins are required for organ growth by supporting the function of the small GTPase Ras homolog enriched in the brain (Rheb) during mTORC1 (mTOR complex 1) signaling. Here we demonstrate that Drosophila GOLPH3 (dGOLPH3) physically interacts with Tctp and 14-3-3ζ. RNAi-mediated knockdown of dGOLPH3 reduces wing and eye size and enhances the phenotypes of Tctp RNAi. This phenotype is partially rescued by overexpression of Tctp, 14-3-3ζ, or Rheb. We also show that the Golgi localization of Rheb in Drosophila cells depends on dGOLPH3. Consistent with dGOLPH3 involvement in Rheb-mediated mTORC1 activation, depletion of dGOLPH3 also reduces levels of phosphorylated ribosomal S6 kinase, a downstream target of mTORC1. Finally, the autophagy flux and the expression of autophagic transcription factors of the TFEB family, which anti correlates with mTOR signaling, are compromised upon reduction of dGOLPH3. Overall, our data provide the first in vivo demonstration that GOLPH3 regulates organ growth by directly associating with mTOR signaling proteins.

GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila / Frappaolo, Anna; KARIMPOUR GHAHNAVIEH, Angela; Cesare, Giuliana; Sechi, Stefano; Fraschini, Roberta; Vaccari, Thomas; Giansanti, Maria Grazia. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 13:11(2022), pp. 1-12. [10.1038/s41419-022-05438-9]

GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila

Anna Frappaolo
Co-primo
;
Angela Karimpour Ghahnavieh
Co-primo
;
Thomas Vaccari;Maria Grazia Giansanti
2022

Abstract

The oncoprotein GOLPH3 (Golgi phosphoprotein 3) is an evolutionarily conserved phosphatidylinositol 4-phosphate effector, mainly localized to the Golgi apparatus, where it supports organelle architecture and vesicular trafficking. Overexpression of human GOLPH3 correlates with poor prognosis in several cancer types and is associated with enhanced signaling downstream of mTOR (mechanistic target of rapamycin). However, the molecular link between GOLPH3 and mTOR remains elusive. Studies in Drosophila melanogaster have shown that Translationally controlled tumor protein (Tctp) and 14-3-3 proteins are required for organ growth by supporting the function of the small GTPase Ras homolog enriched in the brain (Rheb) during mTORC1 (mTOR complex 1) signaling. Here we demonstrate that Drosophila GOLPH3 (dGOLPH3) physically interacts with Tctp and 14-3-3ζ. RNAi-mediated knockdown of dGOLPH3 reduces wing and eye size and enhances the phenotypes of Tctp RNAi. This phenotype is partially rescued by overexpression of Tctp, 14-3-3ζ, or Rheb. We also show that the Golgi localization of Rheb in Drosophila cells depends on dGOLPH3. Consistent with dGOLPH3 involvement in Rheb-mediated mTORC1 activation, depletion of dGOLPH3 also reduces levels of phosphorylated ribosomal S6 kinase, a downstream target of mTORC1. Finally, the autophagy flux and the expression of autophagic transcription factors of the TFEB family, which anti correlates with mTOR signaling, are compromised upon reduction of dGOLPH3. Overall, our data provide the first in vivo demonstration that GOLPH3 regulates organ growth by directly associating with mTOR signaling proteins.
2022
GOLPH3, mTOR, Golgi, organ growth
01 Pubblicazione su rivista::01a Articolo in rivista
GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila / Frappaolo, Anna; KARIMPOUR GHAHNAVIEH, Angela; Cesare, Giuliana; Sechi, Stefano; Fraschini, Roberta; Vaccari, Thomas; Giansanti, Maria Grazia. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 13:11(2022), pp. 1-12. [10.1038/s41419-022-05438-9]
File allegati a questo prodotto
File Dimensione Formato  
Frappaolo_GOLPH3_2022.pdf

accesso aperto

Note: GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila
Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 4.66 MB
Formato Adobe PDF
4.66 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1672140
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 8
social impact