Mucus supramolecular topology: An elusive riddle

Verdugo, Pedro

doi:10.1073/pnas.1211117109

Cited by 10 publications

(11 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unpacking of such granulae involves bicarbonate-mediated removal of Ca 2+ . When studying goblet cells during MUC2 unpacking, we observed the ringlike structures (4) that Verdugo suggests to be crosslinking artifacts (2). Fixation for EM might cause artifacts, but these rings are in line with the findings of other experiments, supporting our model.…”

supporting

confidence: 80%

“…Our observation that this stratified layer can be converted into the outer mucus layer by a three-to fivefold 3D swelling caused by MUC2 mucin proteolysis shows that a mucin can be transformed into other mucus forms (6). The outer colon mucus layer is more typical for mucus and shows that our model is compatible with 3D swelling as referred to by Verdugo (2). The MUC2 mucin of the small intestine does not form stratified mucus, and we now know this is also a result of specific proteolysis in the MUC2 mucin.…”

supporting

confidence: 72%

“…Our view of MUC2 packing is largely based on the recent understanding of von Willebrand factor (vWF), a molecule that evolved from the mucins and has a to mucins similar domain organization in its N-terminal 1,200 aa (5). vWF is packed as linear spirals, and glutaraldehyde cross-linking of endothelial cells with Weibel-Palade bodies shows EM with tubular structures (5) and not interconnected polygonal structures as stated by Verdugo (2). Release of vWF is by a slow unwinding of the linear polymer as it is pulled out from the vesicle by the vascular blood flow.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Reply to Verdugo: Mucins form highly organized supramolecular structures

Ambort¹,

Hansson²

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The model of mucins as enormously large linear polymers with limited organization has dominated the mucus field. Twenty-five years ago, Verdugo et al. (1) suggested that the mucins are stored as such in the regulated secretory pathway of goblet cells and packed by calcium ions shielding the negative charges (sialic acid and sulfate groups) of the highly glycosylated mucin domains (1, 2). That Ca 2+ and low pH are necessary for packing mucins is not controversial, as this is the case for all cell types with regulated secretory machinery. Typical for such granulae, including goblet cells, as shown by Tetsuji et al. (3) and referred to by Verdugo (2), are packed electron-dense protein cores often without discernible structure. Unpacking of such granulae involves bicarbonate-mediated removal of Ca 2+ . When studying goblet cells during MUC2 unpacking, we observed the ringlike structures (4) that Verdugo suggests to be crosslinking artifacts (2). Fixation for EM might cause artifacts, but these rings are in line with the findings of other experiments, supporting our model. Our view of MUC2 packing is largely based on the recent understanding of von Willebrand factor (vWF), a molecule that evolved from the mucins and has a to mucins similar domain organization in its N-terminal 1,200 aa (5). vWF is packed as linear spirals, and glutaraldehyde cross-linking of endothelial cells with Weibel-Palade bodies shows EM with tubular structures (5) and not interconnected polygonal structures as stated by Verdugo (2). Release of vWF is by a slow unwinding of the linear polymer as it is pulled out from the vesicle by the vascular blood flow. This is in contrast to the mucin release in which the packed mucin is expanded 1,000-fold in seconds. This process requires a well-organized packing in the storage granulae such as the one suggested by our model with N-terminal trimers packed with the help of Ca 2+ ions into concatenated rings (4). TheVerdugo model (2) with randomly packed mucins is not compatible with such a fast release without entanglements. The released MUC2 mucin will produce relatively flat sheets that we suggest are staggered on top of each other (4). However, we have claimed this is the case for only the inner mucus layer of colon, in which this suits its function to separate the intestinal bacteria from the epithelial cells (6). Our observation that this stratified layer can be converted into the outer mucus layer by a three-to fivefold 3D swelling caused by MUC2 mucin proteolysis shows that a mucin can be transformed into other mucus forms (6). The outer colon mucus layer is more typical for mucus and shows that our model is compatible with 3D swelling as referred to by Verdugo (2). The MUC2 mucin of the small intestine does not form stratified mucus, and we now know this is also a result of specific proteolysis in the MUC2 mucin. It should, however, be pointed out that it is possible that the other human gel-forming mucins (MUC5AC, MUC5B, and MUC6) do not follow our MUC2 model.

show abstract

supporting

confidence: 80%

supporting

confidence: 72%

mentioning

confidence: 99%

See 1 more Smart Citation

Reply to Verdugo: Mucins form highly organized supramolecular structures

Ambort¹,

Hansson²

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In brief, MUC2 dimers are reported to polymerise via N-terminal trimerisation to yield branched polymers (Ambort et al , 2012, Godl et al , 2002), whereas MUC5B and MUC5AC dimers polymerise via N-terminal dimerisation to form linear polymers (Ridley et al , 2011, Round et al , 2004, Sheehan et al , 2004, Thornton et al , 1990). Whatever the mechanism of polymer assembly, it has become increasingly clear that mucin polymers are highly organised within the secretory granules (Ambort et al , 2012, Kesimer et al , 2010), and that this is necessary in order to control their rapid expansion after secretion into the extracellular environment to form mucus (see Verdugo 2012a for an in-depth discussion of the biophysics and dynamics of post-secretory mucin expansion).…”

Section: Polymeric Gel-forming Mucinsmentioning

confidence: 99%

“…These authors proposed a novel model for the highly organised packing of MUC2 within the granule, and how this facilitates the unpacking necessary to form the lamellar structure reported for MUC2-rich mucin gels (Round et al , 2012). However, this model remains controversial and is incompatible with the swelling kinetics and behaviour of mucins as they expand after secretion (Verdugo, 2012a, b). Moreover, whether this model can be generalized to MUC5AC and MUC5B, which form linear rather than branched polymers, has yet to be determined.…”

Section: Polymeric Gel-forming Mucinsmentioning

confidence: 99%

Cystic fibrosis: An inherited disease affecting mucin-producing organs

Ehré

Ridley

Thornton

2014

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Our current understanding of cystic fibrosis (CF) has revealed that the biophysical properties of mucus play a considerable role in the pathogenesis of the disease in view of the fact that most mucus-producing organs are affected in CF patients. In this review, we discuss the potential causal relationship between altered cystic fibrosis transmembrane conductance regulator (CFTR) function and the production of mucus with abnormal biophysical properties in the intestine and lungs, highlighting what has been learned from cell cultures and animal models that mimic CF pathogenesis. A similar cascade of events, including mucus obstruction, infection and inflammation, is common to all epithelia affected by impaired surface hydration. Hence, the main structural components of mucus, namely the polymeric, gel-forming mucins, are critical to the onset of the disease. Defective CFTR leads to epithelial surface dehydration, altered pH/electrolyte composition and mucin concentration. Further, it can influence mucin transition from the intracellular to extracellular environment, potentially resulting in aberrant mucus gel formation. While defective HCO3− production has long been identified as a feature of CF, it has only recently been considered as a key player in the transition phase of mucins. We conclude by examining the influence of mucins on the biophysical properties of CF sputum and discuss existing and novel therapies aimed at removing mucus from the lungs.

show abstract

Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium

Brandolini

Antonosante

Villa

et al. 2017

Journal Cellular Physiology

View full text Add to dashboard Cite

Ketoprofen L-lysine salt (KLS), is widely used due to its analgesic efficacy and tolerability, and L-lysine was reported to increase the solubility and the gastric tolerance of ketoprofen. In a recent report, L-lysine salification has been shown to exert a gastroprotective effect due to its specific ability to counteract the NSAIDs-induced oxidative stress and up-regulate gastroprotective proteins. In order to derive further insights into the safety and efficacy profile of KLS, in this study we additionally compared the effect of lysine and arginine, another amino acid counterion commonly used for NSAIDs salification, in control and in ethanol challenged human gastric mucosa model. KLS is widely used for the control of post-surgical pain and for the management of pain and fever in inflammatory conditions in children and adults. It is generally well tolerated in pediatric patients, and data from three studies in >900 children indicate that oral administration is well tolerated when administered for up to 3 weeks after surgery. Since only few studies have so far investigated the effect of ketoprofen on gastric mucosa maintenance and adaptive mechanisms, in the second part of the study we applied the cMap approach to compare ketoprofen-induced and ibuprofen-induced gene expression profiles in order to explore compound-specific targeted biological pathways. Among the several genes exclusively modulated by ketoprofen, our attention was particularly focused on genes involved in the maintenance of gastric mucosa barrier integrity (cell junctions, morphology, and viability). The hypothesis was further validated by Real-time PCR.

show abstract

Mucus supramolecular topology: An elusive riddle

Cited by 10 publications

References 5 publications

Reply to Verdugo: Mucins form highly organized supramolecular structures

Reply to Verdugo: Mucins form highly organized supramolecular structures

Cystic fibrosis: An inherited disease affecting mucin-producing organs

Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium

Contact Info

Product

Resources

About