Rab6a/a' are important Golgi regulators of pro-inflammatory TNF secretion in macrophages

Micaroni, Massimo, Stanley, Amanda C., Khromykh, Tatiana, Venturato, Juliana, Wong, Colin X. F., Lim, Jet P., Marsh, Brad J., Storrie, Brian, Gleeson, Paul A. and Stow, Jennifer L. (2013) Rab6a/a' are important Golgi regulators of pro-inflammatory TNF secretion in macrophages. PloS One, 8 2: e57034.1-e57034.17. doi:10.1371/journal.pone.0057034


Author Micaroni, Massimo
Stanley, Amanda C.
Khromykh, Tatiana
Venturato, Juliana
Wong, Colin X. F.
Lim, Jet P.
Marsh, Brad J.
Storrie, Brian
Gleeson, Paul A.
Stow, Jennifer L.
Title Rab6a/a' are important Golgi regulators of pro-inflammatory TNF secretion in macrophages
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-02
Sub-type Article (original research)
DOI 10.1371/journal.pone.0057034
Open Access Status DOI
Volume 8
Issue 2
Start page e57034.1
End page e57034.17
Total pages 17
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2014
Language eng
Abstract Lipopolysaccharide (LPS)-activated macrophages secrete pro-inflammatory cytokines, including tumor necrosis factor (TNF) to elicit innate immune responses. Secretion of these cytokines is also a major contributing factor in chronic inflammatory disease. In previous studies we have begun to elucidate the pathways and molecules that mediate the intracellular trafficking and secretion of TNF. Rab6a and Rab6a' (collectively Rab6) are trans-Golgi-localized GTPases known for roles in maintaining Golgi structure and Golgi-associated trafficking. We found that induction of TNF secretion by LPS promoted the selective increase of Rab6 expression. Depletion of Rab6 (via siRNA and shRNA) resulted in reorganization of the Golgi ribbon into more compact structures that at the resolution of electron microcopy consisted of elongated Golgi stacks that likely arose from fusion of smaller Golgi elements. Concomitantly, the delivery of TNF to the cell surface and subsequent release into the media was reduced. Dominant negative mutants of Rab6 had similar effects in disrupting TNF secretion. In live cells, Rab6-GFP were localized on trans-Golgi network (TGN)-derived tubular carriers demarked by the golgin p230. Rab6 depletion and inactive mutants altered carrier egress and partially reduced p230 membrane association. Our results show that Rab6 acts on TNF trafficking at the level of TGN exit in tubular carriers and our findings suggest Rab6 may stabilize p230 on the tubules to facilitate TNF transport. Both Rab6 isoforms are needed in macrophages for Golgi stack organization and for the efficient post-Golgi transport of TNF. This work provides new insights into Rab6 function and into the role of the Golgi complex in cytokine secretion in inflammatory macrophages.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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