RGD Reference Report - ST6Gal-I regulates macrophage apoptosis via alpha2-6 sialylation of the TNFR1 death receptor. - Rat Genome Database

Send us a Message

Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

ST6Gal-I regulates macrophage apoptosis via alpha2-6 sialylation of the TNFR1 death receptor.

Authors: Liu, Z  Swindall, AF  Kesterson, RA  Schoeb, TR  Bullard, DC  Bellis, SL 
Citation: Liu Z, etal., J Biol Chem. 2011 Nov 11;286(45):39654-62. doi: 10.1074/jbc.M111.276063. Epub 2011 Sep 19.
RGD ID: 10043116
Pubmed: PMID:21930713   (View Abstract at PubMed)
PMCID: PMC3234788   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.276063   (Journal Full-text)

Macrophages play a central role in innate immunity, however mechanisms regulating macrophage survival are not fully understood. Herein we describe a novel apoptotic pathway involving alpha2-6 sialylation of the TNFR1 death receptor by the ST6Gal-I sialyltransferase. Variant glycosylation of TNFR1 has not previously been implicated in TNFR1 function, and little is known regarding the TNFR1 glycan composition. To study sialylation in macrophages, we treated U937 monocytic cells with PMA, which stimulates both macrophage differentiation and apoptosis. Interestingly, macrophage differentiation induces ST6Gal-I down-regulation, leading to reduced alpha2-6 sialylation of selected receptors. To prevent loss of alpha2-6 sialylation, we forced constitutive expression of ST6Gal-I, and found that this strongly inhibited PMA-induced apoptosis. Given that PMA-mediated apoptosis is thought to result from up-regulation of TNFalpha, which then activates TNFR1, we next evaluated the alpha2-6 sialylation of TNFR1. U937 cells with forced ST6Gal-I displayed TNFR1 with elevated alpha2-6 sialylation, and this was associated with diminished TNFalpha-stimulated apoptosis. Correspondingly, removal of alpha2-6 sialylation from TNFR1 through either neuraminidase treatment or expression of ST6Gal-I shRNA markedly enhanced TNFalpha-mediated apoptosis. To confirm the physiologic importance of TNFR1 sialylation, we generated overexpressing ST6Gal-I transgenic mice. Peritoneal macrophages from transgenic lines displayed TNFR1 with elevated alpha2-6 sialylation, and these cells were significantly protected against TNFalpha-stimulated apoptosis. Moreover, greater numbers of thioglycollate-induced peritoneal cells were observed in transgenic mice. These collective results highlight a new mechanism of TNFR1 regulation, and further intimate that loss of alpha2-6 sialylation during macrophage differentiation may limit macrophage lifespan by sensitizing cells to TNFalpha-stimulated apoptosis.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
St6gal1  (ST6 beta-galactoside alpha-2,6-sialyltransferase 1)

Additional Information