Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion.
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.
Low
Pei Ching
PC
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Misaki
Ryo
R
Schroder
Kate
K
Stanley
Amanda C
AC
Sweet
Matthew J
MJ
Teasdale
Rohan D
RD
Vanhaesebroeck
Bart
B
Meunier
Frédéric A
FA
Taguchi
Tomohiko
T
Stow
Jennifer L
JL
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D034281:Dynamins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D055571:Secretory Pathway / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D021601:trans-Golgi Network / Q000187:drug effects / Q000201:enzymology
D058534:Class I Phosphatidylinositol 3-Kinases; D034281:Dynamins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C421683:Pik3cd protein, mouse