Chromogranin B (secretogranin I), a neuroendocrine-regulated secretory protein, is sorted to exocrine secretory granules in transgenic mice

Natori, Shoichi; King, Angus; Hellwig, Andrea; Weiß, Ursula; Iguchi, Haruo; Tsuchiya, Benio; Kameya, Toru; Takayanagi, Ryoichi; Nawata, Hajime; Huttner, Wieland B.

doi:10.1093/emboj/17.12.3277

Cited by 26 publications

(13 citation statements)

References 53 publications

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“…This would require packaging of the maturase into the nascent micronemes where processing would occur in a manner akin to prohormone convertase processing of substrates in immature secretory granules (ISGs) (Molinete et al, 2000;Hook and Metz-Boutigue, 2002). A distinction here, however, is that ISGs are derived from condensing vacuoles that bud from the TGN (Natori et al, 1998). Alternatively, if the proTgM2AP-positive compartment is distinct from early endosomes, its juxtaposition suggests that it might be the equivalent of recycling endosomes or late endosomes in T. gondii.…”

Section: Discussionmentioning

confidence: 99%

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

Harper

Huynh

Coppens

et al. 2006

MBoC

101

150

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Propeptides regulate protein function and trafficking in many eukaryotic systems and have emerged as important features of regulated secretory proteins in parasites of the phylum Apicomplexa. Regulated protein secretion from micronemes and host cell invasion are inextricably linked and essential processes for the apicomplexan parasite Toxoplasma gondii. TgM2AP is a propeptide-containing microneme protein found in a heterohexameric complex with the microneme protein TgMIC2, a protein that has a demonstrated fundamental role in gliding motility and invasion. TgM2AP function is also central to these processes, because disruption of TgM2AP (m2apKO) results in secretory retention of TgMIC2, leading to reduced TgMIC2 secretion from the micronemes and impaired invasion. Because the TgM2AP propeptide is predicted to be processed in an intracellular site near where TgMIC2 is retained in m2apKO parasites, we hypothesized that the propeptide and its proteolytic removal influence trafficking and secretion of the complex. We found that proTgM2AP traffics through endosomal compartments and that deletion of the propeptide leads to defective trafficking of the complex within or near this site, resulting in aberrant processing and decreased secretion of TgMIC2, impaired invasion, and reduced virulence in vivo, mirroring the phenotypes observed in m2apKO parasites. In contrast, mutation of several cleavage site residues resulted in normal localization, but it affected the stability and secretion of the complex from the micronemes. Therefore, the propeptide and its cleavage site influence distinct aspects of TgMIC2-M2AP function, with both impacting the outcome of infection. INTRODUCTIONEukaryotic secretory proteins use an assortment of luminal or cytoplasmic forward targeting signals to navigate the secretory system for eventual delivery to the extracellular environment. Among the least well understood of the luminal signals are cleavable elements known as propeptides, which are typically positioned either internally or, more commonly, at the N terminus of a protein. Propeptides have been shown to serve in several capacities. They can facilitate the folding of their cognate protein, regulate its activity or oligomeric assembly, or direct it to a particular intracellular compartment within the endolysosomal or secretory system. For proproteins destined for the regulated secretory pathway, proteolytic processing (also termed proteolytic maturation) typically accompanies the condensation of immature secretory granule contents (Orci et al., 1987;Kuiper and Martens, 2000). Yet, the precise role of proteolytic maturation in the biogenesis and discharge of regulated secretory organelles remains contentious (Arvan and Halban, 2004).Toxoplasma gondii, the etiological agent of toxoplasmosis, is a genetically tractable protozoan parasite that causes widespread infection in humans resulting in significant economic losses worldwide (Jones et al., 2001). As a member of the phylum Apicomplexa, T. gondii features a distinct apical complex consis...

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Section: Discussionmentioning

confidence: 99%

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

Harper

Huynh

Coppens

et al. 2006

MBoC

101

150

View full text Add to dashboard Cite

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“…Thus, many of the experiments performed in endocrine cells to define sorting mechanisms and signals are not possible in primary parotid cells or tissue culture. Regulated secretory proteins are typically sorted to the regulated secretory pathway in foreign secretory cells (Burgess et al, 1985;Natori et al, 1998). Thus, the study of salivary protein secretion in non-salivary cells may provide information on protein-specific processes, although caution is warranted due to differences between cell types (Gorr et al, 2001).…”

Section: (Iv) Secretion Of Salivary Proteins From Non-salivary Cell Tmentioning

confidence: 99%

Parotid Secretory Granules: Crossroads of Secretory Pathways and Protein Storage

2005

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Saliva plays an important role in digestion, host defense, and lubrication. The parotid gland contributes a variety of secretory proteins-including amylase, proline-rich proteins, and parotid secretory protein (PSP)-to these functions. The regulated secretion of salivary proteins ensures the availability of the correct mix of salivary proteins when needed. In addition, the major salivary glands are targets for gene therapy protocols aimed at targeting therapeutic proteins either to the oral cavity or to circulation. To be successful, such protocols must be based on a solid understanding of protein trafficking in salivary gland cells. In this paper, model systems available to study the secretion of salivary proteins are reviewed. Parotid secretory proteins are stored in large dense-core secretory granules that undergo stimulated secretion in response to extracellular stimulation. Secretory proteins that are not stored in large secretory granules are secreted by either the minor regulated secretory pathway, constitutive secretory pathways (apical or basolateral), or the constitutive-like secretory pathway. It is proposed that the maturing secretory granules act as a distribution center for secretory proteins in salivary acinar cells. Protein distribution or sorting is thought to involve their selective retention during secretory granule maturation. Unlike regulated secretory proteins in other cell types, salivary proteins do not exhibit calcium-induced aggregation. Instead, sulfated proteoglycans play a role in the storage of secretory proteins in parotid acinar cells. This work suggests that unique sorting and retention mechanisms are responsible for the distribution of secretory proteins to different secretory pathways from the maturing secretory granules in parotid acinar cells.

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“…For expressing proteins in a wide variety of tissues, a CMV promoter can be used. In addition, our own observations (see below) and the data from Natori et al [1] showed that using a CMV promoter can result in a highly specific protein expression in exocrine pancreatic acini. Gene-targeted mice are derived from embryonic stem (ES) cells.…”

Section: Introductionmentioning

confidence: 66%

Pathophysiology of Acute Experimental Pancreatitis: Lessons from Genetically Engineered Animal Models and New Molecular Approaches

Schäfer¹,

Tietz²,

Göke³

2005

Digestion

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The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field.

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Chromogranin B (secretogranin I), a neuroendocrine-regulated secretory protein, is sorted to exocrine secretory granules in transgenic mice

Cited by 26 publications

References 53 publications

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

A Cleavable Propeptide InfluencesToxoplasmaInfection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

Parotid Secretory Granules: Crossroads of Secretory Pathways and Protein Storage

Pathophysiology of Acute Experimental Pancreatitis: Lessons from Genetically Engineered Animal Models and New Molecular Approaches

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