A Potential Role for Drosophila Mucins in Development and Physiology

Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.R egulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3-6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in se...

show abstract

“…1 C, D, F, and G). Like goblet cells of the mammalian digestive tract, PR cells also contain mucins (e.g., Muc26B) (19) (Fig. 1 F and G).…”

Section: Resultsmentioning

confidence: 99%

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

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

View full text Add to dashboard Cite

show abstract

“…genome contains approximately 25 genes encoding chitin-binding domain proteins and 36 genes encoding mucin-like proteins (27). To date, none of these genes have been studied in the context of the PM, and little is known about the role of mucus and the PM in Drosophila gut homeostasis and immunity.…”

Section: Discussionmentioning

confidence: 99%

Genetic evidence for a protective role of the peritrophic matrix against intestinal bacterial infection in Drosophila melanogaster

Kuraishi

Binggeli

Opota

et al. 2011

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

270

241

View full text Add to dashboard Cite

The peritrophic matrix (PM) forms a layer composed of chitin and glycoproteins that lines the insect intestinal lumen. This physical barrier plays a role analogous to that of mucous secretions of the vertebrate digestive tract and is thought to protect the midgut epithelium from abrasive food particles and microbes. Almost nothing is known about PM functions in Drosophila, and its function as an immune barrier has never been addressed by a genetic approach. Here we show that the Drosocrystallin (Dcy) protein, a putative component of the eye lens of Drosophila, contributes to adult PM formation. A loss-of-function mutation in the dcy gene results in a reduction of PM width and an increase of its permeability. Upon bacterial ingestion a higher level of expression of antibacterial peptides was observed in dcy mutants, pointing to an influence of this matrix on bacteria sensing by the Imd immune pathway. Moreover, dcy-deficient flies show an increased susceptibility to oral infections with the entomopathogenic bacteria Pseudomonas entomophila and Serratia marcescens. Dcy mutant flies also succumb faster than wild type upon ingestion of a P. entomophila toxic extract. We show that this lethality is due in part to an increased deleterious action of Monalysin, a pore-forming toxin produced by P. entomophila. Collectively, our analysis of the dcy immune phenotype indicates that the PM plays an important role in Drosophila host defense against enteric pathogens, preventing the damaging action of pore-forming toxins on intestinal cells.gut | innate immunity | insect immunity | entomopathogens

show abstract

“…Although more than 30 Drosophila genes have been annotated as mucin-like proteins (174), the functional relevance of these genes or, more generally, of mucus in the gut has not been investigated.…”

Section: Peritrophic Matrix and Mucusmentioning

confidence: 99%

The Digestive Tract of Drosophila melanogaster

2013

View full text Add to dashboard Cite

The digestive tract plays a central role in the digestion and absorption of nutrients. Far from being a passive tube, it provides the first line of defense against pathogens and maintains energy homeostasis by exchanging neuronal and endocrine signals with other organs. Historically neglected, the gut of the fruit fly Drosophila melanogaster has recently come to the forefront of Drosophila research. Areas as diverse as stem cell biology, neurobiology, metabolism, and immunity are benefitting from the ability to study the genetics of development, growth regulation, and physiology in the same organ. In this review, we summarize our knowledge of the Drosophila digestive tract, with an emphasis on the adult midgut and its functional underpinnings. 377

show abstract

A Potential Role for Drosophila Mucins in Development and Physiology

Cited by 95 publications

References 21 publications

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Genetic evidence for a protective role of the peritrophic matrix against intestinal bacterial infection in Drosophila melanogaster

The Digestive Tract of Drosophila melanogaster

Contact Info

Product

Resources

About