Vertebrate hemicentin-1 interacts physically and genetically with nidogen-2

Hemicentins are large proteins of the extracellular matrix that belong to the fibulin family and play pivotal roles during development and homeostasis of a variety of invertebrate and vertebrate tissues. However, bona fide interaction partners of hemicentins have not been described as yet. Here, applying surface plasmon resonance spectroscopy and co-immunoprecipitation, we identify the basement membrane protein nidogen-2 (NID2) as a binding partner of mammalian hemicentin-1 (HMCN1), in line with the formerly described essential role of mouse HMCN1 for basement membrane integrity. HMCN1 binds to the same protein domain of NID2 (G2) as formerly shown for laminins, but with an approximately ten-fold lower affinity and in a competitive manner. Immunofluorescence and immunogold labellings reveal that HMCN1/Hmcn1 is localized closely attached to basement membranes and in partial overlap with NID2/Nid2a in different tissues of mouse and zebrafish. Genetic knockout and antisense-mediated knockdown studies in zebrafish further show that loss of Nid2a leads to similar defects in fin fold morphogenesis as loss of Laminin-alpha5 (Lama5) or Hmcn1. Combined partial loss-of-function studies further indicate that nid2a genetically interacts with both hmcn1 and lama5. Together, this suggests that despite their mutually exclusive physical binding, hemicentins, nidogens and laminins tightly cooperate and support each other during formation, maintenance and function of basement membranes to confer tissue linkage.

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Extracellular chloride signals collagen IV network assembly during basement membrane formation

The Journal of Cell Biology ◽

10.1083/jcb.201510065 ◽

2016 ◽

Vol 213 (4) ◽

pp. 479-494 ◽

Cited By ~ 32

Author(s):

Christopher F. Cummings ◽

Vadim Pedchenko ◽

Kyle L. Brown ◽

Selene Colon ◽

Mohamed Rafi ◽

...

Keyword(s):

Cell Culture ◽

Basement Membrane ◽

Collagen Iv ◽

Atomic Level ◽

Basement Membranes ◽

Tissue Architecture ◽

Dynamic Interactions ◽

Conformational Switch ◽

And Function ◽

Fundamental Mechanism

Basement membranes are defining features of the cellular microenvironment; however, little is known regarding their assembly outside cells. We report that extracellular Cl− ions signal the assembly of collagen IV networks outside cells by triggering a conformational switch within collagen IV noncollagenous 1 (NC1) domains. Depletion of Cl− in cell culture perturbed collagen IV networks, disrupted matrix architecture, and repositioned basement membrane proteins. Phylogenetic evidence indicates this conformational switch is a fundamental mechanism of collagen IV network assembly throughout Metazoa. Using recombinant triple helical protomers, we prove that NC1 domains direct both protomer and network assembly and show in Drosophila that NC1 architecture is critical for incorporation into basement membranes. These discoveries provide an atomic-level understanding of the dynamic interactions between extracellular Cl− and collagen IV assembly outside cells, a critical step in the assembly and organization of basement membranes that enable tissue architecture and function. Moreover, this provides a mechanistic framework for understanding the molecular pathobiology of NC1 domains.

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Peroxidasin-mediated bromine enrichment of basement membranes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007749117 ◽

2020 ◽

Vol 117 (27) ◽

pp. 15827-15836

Author(s):

Cuiwen He ◽

Wenxin Song ◽

Thomas A. Weston ◽

Caitlyn Tran ◽

Ira Kurtz ◽

...

Keyword(s):

Basement Membrane ◽

Knockout Mice ◽

Structural Integrity ◽

Secondary Ion Mass Spectrometry ◽

Human Kidney ◽

Collagen Iv ◽

Basement Membranes ◽

Basement Membrane Protein ◽

Mammalian Tissues ◽

Cross Links

Bromine and peroxidasin (an extracellular peroxidase) are essential for generating sulfilimine cross-links between a methionine and a hydroxylysine within collagen IV, a basement membrane protein. The sulfilimine cross-links increase the structural integrity of basement membranes. The formation of sulfilimine cross-links depends on the ability of peroxidasin to use bromide and hydrogen peroxide substrates to produce hypobromous acid (HOBr). Once a sulfilimine cross-link is created, bromide is released into the extracellular space and becomes available for reutilization. Whether the HOBr generated by peroxidasin is used very selectively for creating sulfilimine cross-links or whether it also causes oxidative damage to bystander molecules (e.g., generating bromotyrosine residues in basement membrane proteins) is unclear. To examine this issue, we used nanoscale secondary ion mass spectrometry (NanoSIMS) imaging to define the distribution of bromine in mammalian tissues. We observed striking enrichment of bromine (79Br,81Br) in basement membranes of normal human and mouse kidneys. In peroxidasin knockout mice, bromine enrichment of basement membranes of kidneys was reduced by ∼85%. Proteomic studies revealed bromination of tyrosine-1485 in the NC1 domain of α2 collagen IV from kidneys of wild-type mice; the same tyrosine was brominated in collagen IV from human kidney. Bromination of tyrosine-1485 was reduced by >90% in kidneys of peroxidasin knockout mice. Thus, in addition to promoting sulfilimine cross-links in collagen IV, peroxidasin can also brominate a bystander tyrosine. Also, the fact that bromine enrichment is largely confined to basement membranes implies that peroxidasin activity is largely restricted to basement membranes in mammalian tissues.

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"BM180": a novel basement membrane protein with a role in stimulus-secretion coupling by lacrimal acinar cells

AJP Cell Physiology ◽

10.1152/ajpcell.1996.270.6.c1743 ◽

1996 ◽

Vol 270 (6) ◽

pp. C1743-C1750 ◽

Cited By ~ 20

Author(s):

G. W. Laurie ◽

J. D. Glass ◽

R. A. Ogle ◽

C. M. Stone ◽

J. R. Sluss ◽

...

Keyword(s):

Basement Membrane ◽

Membrane Protein ◽

Acinar Cells ◽

Basement Membranes ◽

Enzyme Linked Immunosorbent Assay ◽

Regulated Secretion ◽

Basement Membrane Protein ◽

Stimulus Secretion Coupling ◽

Lacrimal Acinar Cells ◽

Laminin 1

Regulated secretion requires the developmental coupling of neuronal or hormonal stimuli to an exocytotic response, a multistep pathway whose appearance may be linked with cellular adhesion to the newly formed exocrine cell basement membrane. We screened for adhesion-associated coupling activity using lacrimal acinar cells and have identified “BM180”, a novel basement membrane protein enriched in guanidine HCl extracts of lacrimal and parotid exocrine secretory glands. BM180 resides primarily in a previously inexamined lower molecular-mass basement membrane peak (peak 2) that contains cell adhesion activity inhibitable with the anti-BM180 monoclonal antibody 3E12. Removal of peak 2 by gel filtration or preincubation of basement membrane with 3E12 decreased regulated peroxidase secretion by one-half without affecting constitutive secretion or the amount of cellular peroxidase available for release. Adding back peak 2 restored regulated secretion in a dose-dependent and 3E12-inhibitable manner and suggested a synergistic relationship between BM180 and laminin 1. BM180 has a mobility of 180 and 60 kDa in the absence or presence of dithiothreitol, respectively, and shows no immunological identity by competitive enzyme-linked immunosorbent assay with laminin 1, collagen IV, entactin, fibronectin, BM-40, perlecan, or vitronectin. We propose that BM180 is an important resident of certain glandular basement membranes where it interacts with the cell surface, thereby possibly signaling the appearance of a transducing element in the stimulus-secretion coupling pathway.

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Function of the HYDROXYCINNAMOYL-CoA:SHIKIMATE HYDROXYCINNAMOYL TRANSFERASE is evolutionarily conserved in embryophytes

10.1101/2020.09.16.300285 ◽

2020 ◽

Author(s):

Lucie Kriegshauser ◽

Samuel Knosp ◽

Etienne Grienenberger ◽

Kanade Tatsumi ◽

Desirée D. Gütle ◽

...

Keyword(s):

Phenylpropanoid Pathway ◽

Evolutionary Significance ◽

Marchantia Polymorpha ◽

Loss Of Function ◽

In Planta ◽

Critical Function ◽

Acyl Acceptor ◽

Bona Fide ◽

And Function

ABSTRACTThe plant phenylpropanoid pathway generates a major class of specialized metabolites and precursors of essential extracellular polymers that initially appeared upon plant terrestrialization. Despite its evolutionary significance, little is known about the complexity and function of this major metabolic pathway in extant bryophytes, the ancestors of which were the first land plants. Here, we report that the HYDROXYCINNAMOYL-CoA:SHIKIMATE HYDROXYCINNAMOYL TRANSFERASE (HCT) gene, which plays a critical function in the phenylpropanoid pathway during seed plant development, is functionally conserved in Physcomitrium patens (Physcomitrella), in the moss lineage of bryophytes. Phylogenetic analysis indicates that bona fide HCT function emerged in the progenitor of embryophytes. In vitro enzyme assays, moss phenolic pathway reconstitution in yeast and in planta gene inactivation coupled to targeted metabolic profiling, collectively indicate that P. patens HCT (PpHCT), similar to tracheophyte HCT orthologs, uses shikimate as a native acyl acceptor to produce a p-coumaroyl-5-O-shikimate intermediate. Phenotypic and metabolic analyses of loss-of-function mutants show that PpHCT is necessary for the production of caffeate derivatives, including previously reported caffeoyl-threonate esters, and for the formation of an intact cuticle. Deep conservation of HCT function in embryophytes is further suggested by the ability of HCT genes from P. patens and the liverwort Marchantia polymorpha to complement an Arabidopsis thaliana CRISPR/Cas9 hct mutant, and by the presence of phenolic esters of shikimate in representative species of the three bryophyte lineages.

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Novel N-glycosylation in eukaryotes: laminin contains the linkage unit beta-glucosylasparagine

The Journal of Cell Biology ◽

10.1083/jcb.124.6.1071 ◽

1994 ◽

Vol 124 (6) ◽

pp. 1071-1081 ◽

Cited By ~ 34

Author(s):

R Schreiner ◽

E Schnabel ◽

F Wieland

Keyword(s):

Basement Membrane ◽

Cell Surface ◽

Protein Complexes ◽

Chemical Characterization ◽

Basement Membranes ◽

Basement Membrane Protein ◽

Basement Membrane Component ◽

Membrane Protein Complexes ◽

Cell Surface Glycoproteins ◽

Surface Glycoproteins

The linkage unit to protein of N-linked carbohydrate in eukaryotic glycoproteins consists of N-acetylglucosamine, coupled to the amido nitrogen of asparagine. Additional N-glycosyl linkage units have been unequivocally proven to exist only in the cell surface glycoproteins of various bacteria. Based on immunological analyses, isolation and chemical characterization, we report that one of these units, namely glucose linked to asparagine, exists in the mammalian protein laminin, an extracellular basement membrane component. This finding and the occurrence of identical disaccharide structures in archaebacterial cell surface glycoproteins and mammalian basement membrane protein complexes points towards a conserved and distinct function of these extracellular structural elements. In addition, a method is described to uncover a masked epitope in fixed tissues by chemical O-deglycosylation. This has allowed to morphologically localize the antigen beta-Glc-Asn by immunofluorescence to the basement membranes of kidney glomeruli.

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Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser syndrome–associated proteins

The Journal of Cell Biology ◽

10.1083/jcb.201203065 ◽

2012 ◽

Vol 197 (5) ◽

pp. 677-689 ◽

Cited By ~ 24

Author(s):

Daiji Kiyozumi ◽

Makiko Takeichi ◽

Itsuko Nakano ◽

Yuya Sato ◽

Tomohiko Fukuda ◽

...

Keyword(s):

Basement Membrane ◽

Direct Consequence ◽

Basement Membranes ◽

Dystrophic Epidermolysis Bullosa ◽

Membrane Assembly ◽

Fraser Syndrome ◽

Basement Membrane Protein ◽

Integrin Binding Site ◽

Associated Proteins

Dysfunction of the basement membrane protein QBRICK provokes Fraser syndrome, which results in renal dysmorphogenesis, cryptophthalmos, syndactyly, and dystrophic epidermolysis bullosa through unknown mechanisms. Here, we show that integrin α8β1 binding to basement membranes was significantly impaired in Qbrick-null mice. This impaired integrin α8β1 binding was not a direct consequence of the loss of QBRICK, which itself is a ligand of integrin α8β1, because knock-in mice with a mutation in the integrin-binding site of QBRICK developed normally and do not exhibit any defects in integrin α8β1 binding. Instead, the loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1–dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.

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Kinesin-3 and kinesin-1 motors direct basement membrane protein secretion to a basal sub-region of the basolateral plasma membrane in epithelial cells

10.1101/2021.01.31.429062 ◽

2021 ◽

Author(s):

Allison L. Zajac ◽

Sally Horne-Badovinac

Keyword(s):

Basement Membrane ◽

Protein Secretion ◽

Basolateral Membrane ◽

Basement Membranes ◽

Follicular Epithelium ◽

List Type ◽

Secretory Vesicles ◽

Tissue Architecture ◽

Basal Surface ◽

Basement Membrane Protein

SUMMARYBasement membranes (BMs) are sheet-like extracellular matrices that line the basal surfaces of all epithelia. Since BM proteins form networks, they likely need to be secreted near the basal surface. However, the location of their secretion site and how it is selected are unknown. Working in the Drosophila follicular epithelium, we identified two kinesins essential for normal BM formation. Our data suggest the two kinesins work together to transport Rab10+ BM protein-filled secretory vesicles towards the basal surface along the polarized microtubule array common to epithelia. This kinesin transport biases BM protein secretion basally. When kinesins are depleted, BM proteins are mis-secreted to more apical regions of the lateral membrane, creating ectopic BM protein networks between cells that disrupt cell movements and tissue architecture. These results introduce a new transport step in the BM protein secretion pathway and highlight the importance of controlling the sub-cellular exocytic site of network-forming proteins.HighlightsA kinesin-3 and a kinesin-1 are required for normal basement membrane (BM) assemblyKinesins move Rab10+ BM secretory vesicles basally on polarized microtubule arraysTransport biases BM exocytosis to basal subregions of the basolateral membraneLoss of kinesins creates ectopic BM networks that disrupt tissue architecture

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Caenorhabditis elegans Teneurin, ten-1, Is Required for Gonadal and Pharyngeal Basement Membrane Integrity and Acts Redundantly with Integrin ina-1 and Dystroglycan dgn-1

Molecular Biology of the Cell ◽

10.1091/mbc.e08-01-0028 ◽

2008 ◽

Vol 19 (9) ◽

pp. 3898-3908 ◽

Cited By ~ 35

Author(s):

Agnieszka Trzebiatowska ◽

Ulrike Topf ◽

Ursula Sauder ◽

Krzysztof Drabikowski ◽

Ruth Chiquet-Ehrismann

Keyword(s):

Caenorhabditis Elegans ◽

Basement Membrane ◽

Membrane Integrity ◽

Precursor Cells ◽

Basement Membranes ◽

Synthetic Lethal ◽

C Elegans ◽

Somatic Gonad ◽

Genes Encoding ◽

Membrane Components

The Caenorhabditis elegans teneurin ortholog, ten-1, plays an important role in gonad and pharynx development. We found that lack of TEN-1 does not affect germline proliferation but leads to local basement membrane deficiency and early gonad disruption. Teneurin is expressed in the somatic precursor cells of the gonad that appear to be crucial for gonad epithelialization and basement membrane integrity. Ten-1 null mutants also arrest as L1 larvae with malformed pharynges and disorganized pharyngeal basement membranes. The pleiotropic phenotype of ten-1 mutant worms is similar to defects found in basement membrane receptor mutants ina-1 and dgn-1 as well as in the mutants of the extracellular matrix component laminin, epi-1. We show that the ten-1 mutation is synthetic lethal with mutations of genes encoding basement membrane components and receptors due to pharyngeal or hypodermal defects. This indicates that TEN-1 could act redundantly with integrin INA-1, dystroglycan DGN-1, and laminin EPI-1 in C. elegans development. Moreover, ten-1 deletion sensitizes worms to loss of nidogen nid-1 causing a pharynx unattached phenotype in ten-1;nid-1 double mutants. We conclude that TEN-1 is important for basement membrane maintenance and/or adhesion in particular organs and affects the function of somatic gonad precursor cells.

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Genetic interaction between Caenorhabditis elegans teneurin ten-1 and prolyl 4-hydroxylase phy-1 and their function in collagen IV–mediated basement membrane integrity during late elongation of the embryo

Molecular Biology of the Cell ◽

10.1091/mbc.e10-10-0853 ◽

2011 ◽

Vol 22 (18) ◽

pp. 3331-3343 ◽

Cited By ~ 12

Author(s):

Ulrike Topf ◽

Ruth Chiquet-Ehrismann

Keyword(s):

Caenorhabditis Elegans ◽

Basement Membrane ◽

Body Wall ◽

Catalytic Domain ◽

Genetic Interaction ◽

Membrane Integrity ◽

Collagen Iv ◽

Basement Membranes ◽

A Genome ◽

Body Wall Muscles

Teneurins are a family of phylogenetically conserved proteins implicated in pattern formation and morphogenesis. The sole orthologue in Caenorhabditis elegans, ten-1, is important for hypodermal cell migration, neuronal migration, path finding and fasciculation, gonad development, and basement membrane integrity of some tissues. However, the mechanisms of TEN-1 action remain to be elucidated. Using a genome-wide RNA interference approach, we identified phy-1 as a novel interaction partner of ten-1. phy-1 codes for the catalytic domain of collagen prolyl 4-hydroxylase. Loss of phy-1 significantly enhanced the embryonic lethality of ten-1 null mutants. Double-mutant embryos arrested during late elongation with epidermal defects, disruption of basement membranes, and detachment of body wall muscles. We found that deletion of phy-1 caused aggregation of collagen IV in body wall muscles in elongated embryos and triggered the loss of tissue integrity in ten-1 mutants. In addition, phy-1 and ten-1 each genetically interact with genes encoding collagen IV. These findings support a functional mechanism in which loss of ten-1, together with a reduction of assembled and secreted basement membrane collagen IV protein, leads to detachment of the epidermis from muscle cells during late elongation of the embryo when mechanical stress is generated by muscle contractions.

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Current concepts of basement-membrane structure and function

Bioscience Reports ◽

10.1007/bf01114816 ◽

1981 ◽

Vol 1 (11) ◽

pp. 819-842 ◽

Cited By ~ 34

Author(s):

Michael E. Grant ◽

J. Godfrey Heathcote ◽

Roslyn W. Orkin

Keyword(s):

Basement Membrane ◽

Membrane Structure ◽

Structural Models ◽

Structure And Function ◽

Basement Membranes ◽

Molecular Structures ◽

Similar Protein ◽

Membrane Structure And Function ◽

And Function

Conclusion In this brief review we have attempted to describe the known components of basement membranes in relation to the morphology and function of these matrices. Further details of the molecular structures and biosynthesis of these components may be found in original papers and in various reviews (Kefalides, 1973; Spiro, 1976; Kefalides et al., 1979; Heathcote & Grant, 1981). Although basement membranes appear to contain essentially similar protein and carbohydrate moieties, the proportions and organization of these may differ and, in the opinion of the authors, the key to an understanding of basement membranes lies in the recognition of this heterogeneity. At present, structural models of basement membrane are far from satisfactory and should be regarded with reservation.

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