Abstract
Matrix metalloproteinas-9 (MMP-9) is a glycosylated endopeptidase, and hence its processing between the endoplasmic reticulum (ER), Golgi and trans-Golgi (TGN) network remains under a strict control of factors that affect the microtubule (MT) stabilization, and the recruitment and activation of coat and cargo proteins, including ADP-ribosylation factors (Arfs) and protein kinase D (PKD). Here, we report on the factors implicated in the regulation of MMP-9 secretion by salivary gland acinar cells in response to P. gingivalis LPS, and the effect of hormone, ghrelin. We show that the LPS-elicited induction in MMP-9 secretion is associated with the increase in α-tubulin acetylation and the enhancement in MT stabilization, while the modulatory effect of ghrelin is reflected in a decrease in α-tubulin acetylation. Further, the effect of the LPS occurs in concert with up-regulation in Arf-guanine nucleotide exchange factor (GEF)-mediated Arf1 activation and the TGN recruitment of PKD2, while ghrelin exerts the modulatory effect on Arf-GEF activation. Moreover, we reveal that the LPS-induced up-regulation in MMP-9 secretion is reflected in a marked increase in PKCδ-mediated PKD2 phosphorylation on Ser, while the modulatory effect of ghrelin is manifested by the SFK-PTKs-dependent phosphorylation of PKD2 on Tyr. The findings demonstrate that MT stabilization along with Arf-GEF-mediated Arf1/PKD2 activation play a major role in P. gingivalis LPS-induced up-regulation in salivary gland acinar cell MMP-9 secretion, and point the modulatory mode of action by ghrelin.
Highlights
Porphyromonas gingivalis is recognized as a potent periodontopathic pathogen implicated in the etiology of periodontitis, a chronic inflammatory disease that leads to progressive destruction of teeth-supporting tissue and is the major cause of adult tooth loss [1]-[3]
Employing zymography and Western blot analyses of the extracellular levels of Matrix metalloproteinas-9 (MMP-9) released into the incubation medium by the acinar cells exposed to incubation with LPS of periodontopathic bacterium, P. gingivalis, we showed that the effect of the LPS was manifested in a marked up-regulation in MMP-9 secretion, while preincubation with ghrelin elicited a significant reduction in the LPS effect (Figure 1)
We found that the stimulatory effect of the LPS on MMP-9 secretion was susceptible to suppression by a well-known inhibitor of protein glycosylation, Brefeldin A, which produced an additive result on the inhibitory effect of ghrelin
Summary
Porphyromonas gingivalis is recognized as a potent periodontopathic pathogen implicated in the etiology of periodontitis, a chronic inflammatory disease that leads to progressive destruction of teeth-supporting tissue and is the major cause of adult tooth loss [1]-[3]. Studies show that cytoskeleton plays an important role in cell division and motility, and is involved in the intracellular transport and positioning of organelles and vesicles, and its largest component, MTs, have been directly implicated in the regulation of MMP-9 secretion in several different cell systems [11] [15]-[18] These diverse aspects of MT specialization arise from the accumulation of a variety of posttranslational modifications on the tubulin subunits, one of which is α-tubulin acetylation, which is known to affect the binding of MT-associated proteins and cause the enhanced MT stabilization associated with the increased in MMP-9 secretion [11] [15]
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