Abstract
Up-regulation in salivary gland acinar cell MMP-9 secretion in response to proinflammatory challenge by periodontopathic bacterium, P. gingivalis relays heavily on the factors that influence the protein processing at the level of endoplasmic reticulum-to-Golgi trafficking, and occurs in concert with the changes in the stability dynamics of the major cytoskeleton polymeric structures, microtubules (MTs). In this study, we report that P. gingivalis LPS-elicited induction in the acinar cell MMP-9 secretion is accompanied by the enhancement in MT stabilization, while the modulatory influence of peptide hormone, ghrelin, is associated with MT destabilization. Further, we reveal that the changes in MT dynamics induced by the LPS and ghrelin occur through signal-regulated α-tubulin phosphorylation on Ser/Tyr. The LPS effect is reflected in a marked increase in PKCδ-mediated α-tubulin phosphorylation on Ser, whereas the modulatory influence of ghrelin on MT dynamics is manifested in by SFK-dependent phosphorylation of α-tubulin on Tyr. Moreover, we show that that the changes in MT dynamics, conferred by the LPS and ghrelin, affect the Golgi localization of GTP-Arf1 and the recruitment and activation of PKD2. The findings underscore the role of signal-regulated changes in MT stability dynamics through PKCδ/SFK-mediated α-tubulin phosphorylation on Ser/Tyr in controlling the salivary gland acinar cell MMP-9 secretion in response to P. gingivalis LPS as well as its modulation by ghrelin.
Highlights
Porphyromonas gingivalis is a potent periodontopathic pathogen implicated in the etiology of periodontitis, a chronic inflammatory disease that affects about 15% of population and leads to progressive destruction of teeth-supporting tissue, and is a major cause of adult tooth loss [1] [2] [3]
We investigated the nature of factors affecting MT stability dynamics and their influence on regulatory proteins implicated in the control of salivary gland acinar cell MMP-9 secretion in response to P. gingivalis stimulation
By following Arf1 activation and the levels of MMP-9 released into the medium by the acinar cells exposed to incubation with LPS of periodontopathic bacterium, P. gingivalis, in the presence of peptide hormone, ghrelin, in combination with pharmacological agents affecting MT stability, we found that the effect of the LPS, manifested in a substantial up-regulation in Arf1-GTP formation was associated with a marked increase in MMP-9 secretion (Figure 1)
Summary
Porphyromonas gingivalis is a potent periodontopathic pathogen implicated in the etiology of periodontitis, a chronic inflammatory disease that affects about 15% of population and leads to progressive destruction of teeth-supporting tissue, and is a major cause of adult tooth loss [1] [2] [3]. To other regulated secretory proteins, the processing of MMP-9 along the endoplasmic reticulum (ER), Golgi, and trans-Golgi network (TGN) remains under a strict control of factors that affect the membrane recruitment and activation of various coat and cargo proteins, including ADPribosylation factors (Arfs) and protein kinase D (PKD), [9] [10] [11] [12]. While GDP-bound inactive Arfs are cytosolic, the stimulus activated GTP-bound class I Arfs (Arf, Arf, and Arf3) rapidly translocate to the Golgi membrane compartments and assume the principal role in the recruitment of various cytosolic coat and cargo adaptor proteins, exchange factors, and lipid modifying enzymes that are essential for regulation of ER-to-Golgi traffic [11] [12]. The PKD family of serine/threonine kinases (PKD1, PKD2, and PKD3), plays a crucial role in the regulation of Golgi structure and function by phosphorylation of the TGN-localized substrates required for subsequent shedding of cargo-containing vesicles [10]
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