Tetraspanin protein (TSP-15) is required for epidermal integrity in<i>Caenorhabditis elegans</i>

Moribe, Hiroki; Yochem, John; Yamada, Hiromi; Tabuse, Yo; Fujimoto, Toyoshi; Mekada, Eisuke

doi:10.1242/jcs.01403

Cited by 96 publications

(97 citation statements)

References 60 publications

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“…nsy-1 cDNA (Sagasti et al 2001) fused with gfp was subcloned to the region downstream of the dpy-7, vha-6, and unc-119 promoters to form a hypodermal, intestinal, and neuronal rescue construct, respectively (Oka et al 2001;Lesa et al 2003;Moribe et al 2004). The dpy-7 and vha-6 constructs were injected into nsy-1(ky400) mutant animals at a concentration of 5 mg/ml together with the marker construct vha-6Tgfp at 50 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

et al. 2011

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Cells and organisms face anoxia in a wide variety of contexts, including ischemia and hibernation. Cells respond to anoxic conditions through multiple signaling pathways. We report that NSY-1, the Caenorhabditis elegans ortholog of mammalian apoptosis signal-regulating kinase (ASK) family of MAP kinase (MAPK) kinase kinases (MAP3Ks), regulates viability of animals in anoxia. Loss-of-function mutations of nsy-1 increased survival under anoxic conditions, and increased survival was also observed in animals with mutations in tir-1 and the MAPK kinase (MAP2K) sek-1, which are upstream and downstream factors of NSY-1, respectively. Consistent with these findings, anoxia was found to activate the p38 MAPK ortholog PMK-1, and this was suppressed in nsy-1 and tir-1 mutant animals. Furthermore, double-mutant analysis showed that the insulin-signaling pathway, which also regulates viability in anoxia, functioned in parallel to NSY-1. These results suggest that the TIR-1-NSY-1-SEK-1-PMK-1 pathway plays important roles in the reponse to anoxia in C. elegans.

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Section: Methodsmentioning

confidence: 99%

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

et al. 2011

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“…Embryos mutant for the cuticle collagen sqt-3 elongate initially and then retract, revealing a requirement for cuticle to stabilize epidermal cell shape (Priess and Hirsh, 1986). Mutants for the tetraspanin tsp-15, which show various cuticle abnormalities, also show seam epidermal protrusions and junction connectivity defects (Moribe et al, 2004). Finally, sec-23 mutations that impair cuticle secretion (and presumably secretion of eLRRon proteins as well) cause embryonic rupturing at the two-to threefold stage as described here for sym-1; let-4(RNAi) embryos (Roberts et al, 2003).…”

Section: How Might Apical Ecm Organization Affect Epithelial Junctionmentioning

confidence: 99%

Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity inC. elegans

et al. 2012

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SUMMARYEpithelial cells are linked by apicolateral junctions that are essential for tissue integrity. Epithelial cells also secrete a specialized apical extracellular matrix (ECM) that serves as a protective barrier. Some components of the apical ECM, such as mucins, can influence epithelial junction remodeling and disassembly during epithelial-to-mesenchymal transition (EMT). However, the molecular composition and biological roles of the apical ECM are not well understood. We identified a set of extracellular leucine-rich repeat only (eLRRon) proteins in C. elegans (LET-4 and EGG-6) that are expressed on the apical surfaces of epidermal cells and some tubular epithelia, including the excretory duct and pore. A previously characterized paralog, SYM-1, is also expressed in epidermal cells and secreted into the apical ECM. Related mammalian eLRRon proteins, such as decorin or LRRTM1-3, influence stromal ECM or synaptic junction organization, respectively. Mutants lacking one or more of the C. elegans epithelial eLRRon proteins show multiple defects in apical ECM organization, consistent with these proteins contributing to the embryonic sheath and cuticular ECM. Furthermore, epithelial junctions initially form in the correct locations, but then rupture at the time of cuticle secretion and remodeling of cell-matrix interactions. This work identifies epithelial eLRRon proteins as important components and organizers of the pre-cuticular and cuticular apical ECM, and adds to the small but growing body of evidence linking the apical ECM to epithelial junction stability. We propose that eLRRon-dependent apical ECM organization contributes to cell-cell adhesion and may modulate epithelial junction dynamics in both normal and disease situations.

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“…Moreover, CD151 and a homologous tetraspanin, TSP-15, are essential for maintenance of epithelial characteristics (11,12), which is crucial for the development and maintenance of lung structure. However, the involvement of CD151 in lung diseases has remained unclear.…”

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confidence: 99%

Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

Tsujino

Takeda

Arai

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. Methods: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wildtype mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. Measurements and Main Results: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased a-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. Conclusions: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.Keywords: alveolar epithelial cell; adhesion strength; epithelial-tomesenchymal transition; Smad2; CD9 Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology; the condition has a poor prognosis, and there are no effective treatments. IPF is characterized by progressive deposition of collagen and other extracellular matrix (ECM) molecules (1). Previously, IPF was viewed as a "smoldering" inflammatory response that ultimately led to chronic lung injury with subsequent fibrosis. However, inflammation is now not regarded as crucial to the etiology, largely because current antiinflammatory therapies for IPF have provided little benefit for patients (2). Instead, it has become clear that abnormal behavior of alveolar epithelial cells (AECs) is a primary source of the development of pulmonary fibrosis (3, 4). The disease process is initiated through repetitive injury of AECs, causing AEC activation, which in turn leads to recruitment of immune cells and fibroblasts within the lung microenvironment. Aberrant activated AECs, in cooperation with migrated immune cells and fibroblasts, secrete and activate latent transforming growth factor (TGF)-b 1 , as well as other profibrotic factors, which promote the differentiation of fibroblasts and AECs to myofibroblasts, resulting in overproduction of ECM in the lung.The tet...

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Tetraspanin protein (TSP-15) is required for epidermal integrity inCaenorhabditis elegans

Cited by 96 publications

References 60 publications

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity inC. elegans

Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

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