Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion

Pei Ching Low; Ryo Misaki; Kate Schroder; Amanda C Stanley; Matthew J Sweet; Rohan D Teasdale; Bart Vanhaesebroeck; Frédéric A Meunier; Tomohiko Taguchi; Jennifer L Stow

doi:10.1083/jcb.201001028

Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion

J Cell Biol. 2010 Sep 20;190(6):1053-65. doi: 10.1083/jcb.201001028. Epub 2010 Sep 13.

Authors

Pei Ching Low¹, Ryo Misaki, Kate Schroder, Amanda C Stanley, Matthew J Sweet, Rohan D Teasdale, Bart Vanhaesebroeck, Frédéric A Meunier, Tomohiko Taguchi, Jennifer L Stow

Affiliation

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.

Abstract

Phosphoinositide 3-kinase (PI3K) p110 isoforms are membrane lipid kinases classically involved in signal transduction. Lipopolysaccharide (LPS)-activated macrophages constitutively and abundantly secrete proinflammatory cytokines including tumor necrosis factor-α (TNF). Loss of function of the p110δ isoform of PI3K using inhibitors, RNA-mediated knockdown, or genetic inactivation in mice abolishes TNF trafficking and secretion, trapping TNF in tubular carriers at the trans-Golgi network (TGN). Kinase-active p110δ localizes to the Golgi complex in LPS-activated macrophages, and TNF is loaded into p230-labeled tubules, which cannot undergo fission when p110δ is inactivated. Similar blocks in fission of these tubules and in TNF secretion result from inhibition of the guanosine triphosphatase dynamin 2. These findings demonstrate a new function for p110δ as part of the membrane fission machinery required at the TGN for the selective trafficking and secretion of cytokines in macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Survival / drug effects
Class I Phosphatidylinositol 3-Kinases
Dynamins / metabolism
Enzyme Activation / drug effects
Gene Knockdown Techniques
Gene Silencing / drug effects
Golgi Apparatus / drug effects
Golgi Apparatus / enzymology*
Golgi Apparatus / metabolism*
Intracellular Membranes / drug effects
Intracellular Membranes / enzymology
Intracellular Membranes / metabolism*
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Lipopolysaccharides / pharmacology
Macrophages / cytology
Macrophages / drug effects
Macrophages / enzymology
Macrophages / metabolism
Mice
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Protein Transport / drug effects
RNA, Small Interfering / metabolism
Secretory Pathway / drug effects
Tumor Necrosis Factor-alpha / metabolism*
trans-Golgi Network / drug effects
trans-Golgi Network / enzymology

Substances

Isoenzymes
Lipopolysaccharides
Phosphoinositide-3 Kinase Inhibitors
RNA, Small Interfering
Tumor Necrosis Factor-alpha
Class I Phosphatidylinositol 3-Kinases
Pik3cd protein, mouse
Dynamins