DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration?

Kang, Weiqun; Reid, Kenneth B.M.

doi:10.1016/s0014-5793(03)00217-5

Cited by 87 publications

(62 citation statements)

References 49 publications

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“…The most notable case is an apparent 40% expansion of SRCR domains. Many of these domain sequences are similar to those of human DMBT1, a proposed regulator of mucosal homeostasis 78 . This suggests a link between the abundance of SRCR domains in chicken and its adaptive requirements in mucosal defence.…”

Section: Gene and Family Differencesmentioning

confidence: 82%

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

2004

Nature

2,284

1,054

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Section: Gene and Family Differencesmentioning

confidence: 82%

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

2004

Nature

2,284

1,054

View full text Add to dashboard Cite

“…gp340 appears to have diverse functions, being involved in cancer and tissue differentiation as well as in host innate defense and microbial diseases, such as Crohn disease and dental caries (4,8,12,36). In innate immunity, gp340 functions as a scavenger receptor and is suggested to have a role in maintaining mucosal homeostasis by inhibiting bacterial invasion and down-regulating inflammation (5).…”

Section: Discussionmentioning

confidence: 99%

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Loimaranta¹,

Hytönen

Pulliainen

et al. 2009

Journal of Biological Chemistry

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Scavenger receptors are innate immune molecules recognizing and inducing the clearance of non-host as well as modified host molecules. To recognize a wide pattern of invading microbes, many scavenger receptors bind to common pathogenassociated molecular patterns, such as lipopolysaccharides and lipoteichoic acids. Similarly, the gp340/DMBT1 protein, a member of the human scavenger receptor cysteine-rich protein family, displays a wide ligand repertoire. The peptide motif VEVLXXXXW derived from its scavenger receptor cysteine-rich domains is involved in some of these interactions, but most of the recognition mechanisms are unknown. In this study, we used mass spectrometry sequencing, gene inactivation, and recombinant proteins to identify Streptococcus pyogenes protein Human gp340, also known as DMBT1 (deleted in malignant brain tumors 1), belongs to the innate immune protein family of scavenger receptor cysteine-rich (SRCR) 2 proteins, all of which contain one or more evolutionarily conserved SRCR domain linked to other conserved protein domains (1, 2). Many of these proteins serve as pattern recognition receptors for innate immunity. gp340 is expressed by epithelial cells and cells of the immune system, and its expression is up-regulated after inflammatory stimuli (3, 4). It inhibits bacterial invasion to epithelial cells and the secretion of proinflammatory cytokines (5-7).Thus, it appears to be an important mediator of host immune responses to various microbes and was recently linked to Crohn disease, a human inflammatory bowel disease (8). gp340 is also found in human secretions like tears and saliva, and the salivary form has long been known as salivary agglutinin, which is an important molecule in oral biofilm formation and is suggested to have a role in dental caries development (9 -12). The mechanisms of gp340 action in these different biological contexts are not known. Common to all scavenger receptors, the ligand repertoire of gp340 is wide; it binds many different types of bacteria as well as viruses (10,13,14). The wide ligand recognition pattern of scavenger receptors is thought to be based on the recognition of common microbial structures, such as lipopolysaccharides and lipoteichoic acids, but in the case of gp340, specific bacterial surface proteins are reported to be involved in the interactions characterized (15-18). Because the importance of gp340/salivary agglutinin in the oral environment has been evident for a long time, most of our knowledge of gp340-microbial interactions is from studies with oral bacteria. For example, viridans streptococci, such as Streptococcus mutans and Streptococcus gordonii, interact with saliva gp340 via their surface proteins AgI/II and the sialic acid-binding Hsa or GspB adhesin. In these interactions, gp340 shows a peculiar fluid phase versus surfaceadsorbed behavior, as evidenced by AgI/II polypeptides primarily mediating aggregation of bacteria by fluid phase gp340, whereas the Hsa adhesin primarily mediates adhesion of S. gordonii to surface-bound gp340 (18)...

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“…Moreover, different ZP domain proteins with short propeptides ending with an EHP, such as DMBT1 and LZP (Fig. 5), are also secreted (21,38). However, the EHP cannot simply be a secretion signal: even if the EHP ultimately dissociates from the mature protein, its presence at the plasma membrane is required for assembly of secreted, full-length ZP3 constructs (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in genes encoding ZP domain proteins can result in severe human pathologies, including nonsyndromic deafness (18), vascular (19) and renal (20) diseases, and cancer (21,22). Characterization of some of these mutations suggest that, by reducing or abolishing secretion, protein polymerization is affected only indirectly (1).…”

mentioning

confidence: 99%

A duplicated motif controls assembly of zona pellucida domain proteins

Jovine

Williams

et al. 2004

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

126

170

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Many secreted eukaryotic glycoproteins that play fundamental roles in development, hearing, immunity, and cancer polymerize into filaments and extracellular matrices through zona pellucida (ZP) domains. ZP domain proteins are synthesized as precursors containing C-terminal propeptides that are cleaved at conserved sites. However, the consequences of this processing and the mechanism by which nascent proteins assemble are unclear. By microinjection of mutated DNA constructs into growing oocytes and mammalian cell transfection, we have identified a conserved duplicated motif [EHP (external hydrophobic patch)͞IHP (internal hydrophobic patch)] regulating the assembly of mouse ZP proteins. Whereas the transmembrane domain (TMD) of ZP3 can be functionally replaced by an unrelated TMD, mutations in either EHP or IHP do not hinder secretion of full-length ZP3 but completely abolish its assembly. Because mutants truncated before the TMD are not processed, we conclude that the conserved TMD of mammalian ZP proteins does not engage them in specific interactions but is essential for C-terminal processing. Cleavage of ZP precursors results in loss of the EHP, thereby activating secreted polypeptides to assemble by using the IHP within the ZP domain. Taken together, these findings suggest a general mechanism for assembly of ZP domain proteins.T he zona pellucida (ZP) domain is a protein polymerization module of Ϸ260 aa (1). Since its identification in mouse ZP glycoproteins (2), this domain has been found in many extracellular eukaryotic proteins of diverse molecular architecture and biological function (2, 3). These include egg coat proteins, inner ear proteins, urinary and pancreatic proteins, transforming growth factor-␤ receptors, immune defense proteins, nematode cuticle components, and fly proteins involved in transmission of mechanical stimuli and in wing and tracheal morphogenesis (4).We study the ZP (3), an extracellular coat secreted by growing mouse oocytes, as a model for ZP domain protein maturation and assembly. The ZP consists of long filaments composed of ZP2 and ZP3, crosslinked by a third ZP domain protein, ZP1. Nascent ZP polypeptides have features in common with other ZP domain proteins (2-4) that include an N-terminal signal sequence (SP), a ZP domain, and a consensus furin cleavage site (CFCS). The latter is followed by a C-terminal propeptide containing a transmembrane domain (TMD) and short cytoplasmic tail (Fig. 1A) that are replaced by a glycosyl phosphatidylinositol anchor in some ZP domain proteins. During secretion, but before incorporation into the ZP, a furin-like enzyme excises the propeptide from ZP precursors by cleavage at the CFCS (5-8). C-terminal processing of precursors also occurs for ZP homologues from fish to birds (9-11), as well as for other . Recombinant ZP proteins synthesized from cDNAs mutated at the CFCS are not secreted and accumulate in the endoplasmic reticulum of transfected cells (15)(16)(17). Recently, assembly of ZP proteins was studied by microinjection of epitope-tagge...

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DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration?

Cited by 87 publications

References 49 publications

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

A duplicated motif controls assembly of zona pellucida domain proteins

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