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Molecular and Cellular Biology, October 2008, p. 6149-6159, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00220-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of the Endosomal SNARE Protein Syntaxin 7 by Colony-Stimulating Factor 1 in Macrophages{triangledown}

Adrian Achuthan,1 Paul Masendycz,1 Jamie A. Lopez,2 Thao Nguyen,1 David E. James,2 Matthew J. Sweet,3 John A. Hamilton,1 and Glen M. Scholz1*

Department of Medicine and Cooperative Research Centre for Chronic Inflammatory Diseases, The University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia,1 Garvan Institute of Medical Research, Darlinghurst, 2010 Sydney, New South Wales, Australia,2 Institute for Molecular Bioscience and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Queensland, Brisbane, Queensland 4072, Australia3

Received 20 February 2008/ Returned for modification 18 March 2008/ Accepted 7 August 2008

Colony-stimulating factor 1 (CSF-1) is the main growth factor controlling the development of macrophages from myeloid progenitor cells. However, CSF-1 also regulates some of the key effector functions of macrophages (e.g., phagocytosis and cytokine secretion). The endosomal SNARE protein syntaxin 7 (Stx7) regulates vesicle trafficking events involved in phagocytosis and cytokine secretion. Therefore, we investigated the ability of CSF-1 to regulate Stx7. CSF-1 upregulated Stx7 expression in primary mouse macrophages; it also upregulated expression of its SNARE partners Vti1b and VAMP8 but not Stx8. Additionally, CSF-1 induced the rapid serine phosphorylation of Stx7 and enhanced its binding to Vti1b, Stx8, and VAMP8. Bioinformatics analysis and results from experiments with kinase inhibitors suggested the CSF-1-induced phosphorylation of Stx7 was mediated by protein kinase C and Akt in response to phosphatidylinositol 3-kinase activation. Based on mutagenesis studies, CSF-1 appeared to increase the binding of Stx7 to its SNARE partners by inducing the phosphorylation of serine residues in the Habc domain and/or "linker" region of Stx7. Thus, CSF-1 is a key regulator of Stx7 expression and function in macrophages. Furthermore, the effects of CSF-1 on Stx7 may provide a mechanism for the regulation of macrophage effector functions by CSF-1.

* Corresponding author. Mailing address: Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3010, Australia. Phone: 61-3-8344-3298. Fax: 61-3-9347-1863. E-mail: glenms{at}unimelb.edu.au

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6149-6159, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00220-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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