Regulated Airway Goblet Cell Mucin Secretion

Davis, C. William; Dickey, Burton F.

doi:10.1146/annurev.physiol.70.113006.100638

Cited by 212 publications

(241 citation statements)

References 160 publications

(186 reference statements)

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“…Whereas airway mucus protects the epithelial lining by entrapping and clearing foreign debris, bacteria, and viruses from the airway by ciliary movement, a process termed mucociliary clearance (16,17), excessive airway mucus secretion, mucus hypersecretion, may cause mucus accumulation that is associated with human clinical conditions such as asthma and chronic obstructive pulmonary disease where mucus accumulation contributes to respiratory diseases. Mucus secretion is a regulated process coordinated by several molecules, including SNARE proteins, myristoylated alanine-rich C kinase substrate (MARCKS), and Munc proteins, which coordinate the docking of mucin containing vesicles with the secretory cell plasma membrane for exocytosis (16,17). Targeting SNAP23 by a substrate modified BoNT may reduce the secretion processes of hypersecretion syndromes.…”

Section: Discussionmentioning

confidence: 99%

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Engineering botulinum neurotoxin to extend therapeutic intervention

Chen

Barbieri

2009

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

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Clostridium botulinum neurotoxins (BoNTs) are effective therapeutics for a variety of neurological disorders, such as strabismus, blepharospam, hemificial spasm, and cervical dystonia, because of the toxin's tropism for neurons and specific cleavage of neuronal soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptors (SNARE) proteins. Modifying BoNT to bind nonneuronal cells has been attempted to extend therapeutic applications. However, prerequisite to develop nonneuronal therapies requires the retargeting the catalytic activity of BoNTs to nonneuronal SNARE isoforms. Here, we reported the engineering of a BoNT derivative that cleaves SNAP23, a nonneuronal SNARE protein. SNAP23 mediates vesicle-plasma membrane fusion processes, including secretion of airway mucus, antibody, insulin, gastric acids, and ions. This mutated BoNT/E light chain LC/E(K 224 D) showed extended substrate specificity to cleave SNAP23, and the natural substrate, SNAP25, but not SNAP29 or SNAP47. Upon direct protein delivery into cultured human epithelial cells, LC/E(K 224 D) cleaved endogenous SNAP23, which inhibited secretion of mucin and IL-8. These studies show the feasibility of genetically modifying LCs to target a nonneuronal SNARE protein that extends therapeutic potential for treatment of human hypersecretion diseases.Clostridium botulinum neurotoxins (BoNTs) are the most potent protein toxins for humans (1). BoNTs elicit neuronal-specific flaccid paralysis by targeting neurons and cleaving neuronspecific soluble N-ethylmaleimide-sensitive fusion proteinattachment protein receptors (SNARE) proteins. BoNTs are organized into 3 functional domains: an N-terminal zinc-metalloprotease light chain (LC), a translocation domain (HCT), and a C-terminal receptor binding domain (HCR) (1, 2). BoNTs bind luminal domains of synaptic vesicle proteins, upon the fusion of synaptic vesicles with the plasma membrane (3-5). BoNTs are internalized into endosomes and upon acidification, the LC is translocated into the cytoplasm, where SNARE proteins are cleaved (1, 2).Mammalian neuronal exocytosis is driven by the formation of protein complexes between the vesicle SNARE, VAMP2, and the plasma membrane SNAREs, SNAP25 and syntaxin 1a (6). There are 7 serotypes of BoNTs (termed A-G) that cleave specific residues on 1 of 3 SNARE proteins: serotypes B, D, F, and G cleave VAMP-2, serotypes A and E cleave SNAP25, and serotype C cleaves SNAP25 and syntaxin 1a (1). Thus, neuronal specificity is based upon BoNT binding to neurons and cleaving neuronal isoforms of the SNARE proteins. For example, BoNT/A cleaves human SNAP25, but not the human nonneuronal isoform SNAP23 (7,8). The nonneuronal SNARE isoforms are involved in divergent cellular processes, including fusion reactions in cell growth, membrane repair, cytokinesis, and synaptic transmission (reviewed in 9).The reversible nature of muscle function after BoNT intoxication that replace toxin-affected nerves with new nerves (10) has turned the BoNT from a deadly agent to therapies for neu...

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Section: Discussionmentioning

confidence: 99%

“…Prerequisite to develop therapies requires the retargeting of the catalytic activity of the BoNTs to nonneuronal SNARE isoforms. Here, we extend the substrate specificity of BoNT/E by engineering a catalytic derivative that cleaves the nonneuronal SNARE protein, SNAP23, as a platform to develop therapies for nonneuronal human secretory diseases (16,17). …”

mentioning

confidence: 99%

Engineering botulinum neurotoxin to extend therapeutic intervention

Chen

Barbieri

2009

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

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“…Chloride channel blockers, such as niflumic acid (NFA) and its derivatives, reduce mucin secretion and improve airway function in asthma models (28)(29)(30)(31)(32)(33)(34)(35)(36); however, further drug development has been hampered by several factors, including a lack of knowledge about the molecular identity of CaCC (37)(38)(39). Our findings that TMEM16A-CaCC is up-regulated in the airway epithelium of asthmatics and preferentially in secretory cells in several asthma models support the relevance of this molecule as a target for the treatment of this disease.…”

Section: Tmem16a Is Preferentially Expressed In Secretory Cells In Asmentioning

confidence: 99%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

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

303

342

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Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calciumactivated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.A sthma is a significant cause of morbidity and mortality worldwide, and the prevalence of this disease is increasing among all age, sex, and racial groups. Characteristic features of asthma include inflammation, subepithelial fibrosis, hyperplasia of mucus-producing cells, accumulation of mucus within airway lumens, hyperplasia of airway smooth muscle (ASM), and ASM hyperresponsiveness. Together, these symptoms impair lung function by limiting the flow of gases to and from the alveoli in the distal lung.The current standard of care for asthma involves inhaled corticosteroids for the management of inflammation combined with long-acting agonists of β2-adrenergic receptors. Despite this treatment, lung function is not improved in 30-45% of asthmatic patients, and exacerbations continue to be a major problem (reviewed in ref. 1). Asthma can be divided into at least two distinct molecular phenotypes defined by the degree of Th2 inflammation (2, 3). Cytokines, including IL-4 and IL-13, promote airway epithelial mucous cell metaplasia, subepithelial fibrosis, and hyperplasia of smooth muscle in Th2-high asthmatics, and these patients generally show improved lung function with inhaled corticosteroid therapy. A greater understanding of this heterogeneity and the molecular and physiological events that lead to airway remodeling might lead to improved diagnosis and treatment.Calcium-activated chloride channels (CaCCs) have been ascribed numerous cellular functions (reviewed in refs. 4 and 5), among these are epithelial fluid secretion and smooth muscle contraction, both of which contribute to the progression and severity of asthma. Moreover, calcium-activated chloride currents in the airway epithelium are enhanced by the Th2 cytokines IL-4 and IL-13, as well as IFN-γ (6). For these reasons, CaCC is an attractive potential therapeutic target for asthma (7). However, the study of CaCC was impeded by lack of information about the gene(s) encoding this channel. It was only relatively recently that TMEM16A (transmembrane p...

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“…21,22 However, less is known about the regulation of airway-specific secretory processes. In airway epithelial cells, MUC5AC secretion is considered an adaptive response to environmental stimuli such as respiratory viruses, 23 airway allergens, 24 and cigarette smoke.…”

Section: Introductionmentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

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Regulated Airway Goblet Cell Mucin Secretion

Cited by 212 publications

References 160 publications

Engineering botulinum neurotoxin to extend therapeutic intervention

Engineering botulinum neurotoxin to extend therapeutic intervention

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

IL13 activates autophagy to regulate secretion in airway epithelial cells

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