Cell wounding activates phospholipase D in primary mouse keratinocytes

Arun, Senthil Nathan; Xie, Dongdong; Howard, Amber C.; Zhong, Quincy; Zhong, Xiaofeng; McNeil, Paul L.; Bollag, Wendy B.

doi:10.1194/jlr.m027060

Cited by 29 publications

(28 citation statements)

References 43 publications

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“…Furthermore, knock-out mice with a nonsense mutation in PLD4 manifest a phenotype with thin hair and growth retardation [28]. In addition, Arun et al [29] demonstrated the importance of phospholipase family D members in mediating the repair of plasma membrane disruptions in mice keratinocytes emphasising the role of these phospholipid signalling enzymes in membrane function and wound healing. A mutation in a phospholipase-domain containing protein ( PNPLA1 ) results in a severe cornification disorder in dogs, providing evidence for a key role of lipases in the keratinisation process and the metabolism of the epidermal barrier in general [30].…”

Section: Discussionmentioning

confidence: 99%

A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle

Jung¹,

Pausch²,

Langenmayer³

et al. 2014

BMC Genomics

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BackgroundBovine hereditary zinc deficiency (BHZD) is an autosomal recessive disorder of cattle, first described in Holstein-Friesian animals. Affected calves suffer from severe skin lesions and show a poor general health status. Recently, eight calves with the phenotypic appearance of BHZD have been reported in the Fleckvieh cattle population.ResultsIn spite of the similar disease phenotypes, SLC39A4, the gene responsible for BHZD in Holstein-Friesian was excluded as underlying gene for the disorder in the affected Fleckvieh calves. In order to identify the disease-associated region, genotypes of eight affected calves obtained with the Illumina BovineHD BeadChip comprising 777,962 SNPs were contrasted with the genotypes of 1,339 unaffected animals. A strong association signal was observed on chromosome 21 (P = 5.87 × 10-89). Autozygosity mapping in the eight affected animals revealed a common segment of extended homozygosity encompassing 1,023 kb (BTA 21: 70,550,045 - 71,573,501). This region contains 17 genes/transcripts, among them two genes encoding gastro-intestinal zinc transporters (CRIP1, CRIP2). However, no mutation that was compatible with recessive inheritance could be detected in these candidate genes. One of the affected calves was re-sequenced together with 42 unaffected Fleckvieh animals. Analysis of the sequencing data revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism. To confirm the causality, genotypes of the p.W215X-mutation were obtained from 3,650 animals representing three different breeds. None of the unaffected animals was homozygous for the defect allele, while all eight affected calves were homozygous. The deleterious effect of the mutation is manifested in a significantly lower survival rate of descendants from risk matings when compared with the survival rate of descendants from non-risk matings. The deleterious allele has an estimated frequency of 1.1% in the Fleckvieh population.ConclusionOur results provide strong evidence that a newly identified recessive disorder in the Fleckvieh population is caused by a nonsense mutation in PLD4, most likely resulting in an impaired function of the encoded protein. Although the phenotype of affected calves strongly resembles BHZD, a zinc deficiency resulting from malabsorption is unlikely to be responsible for the diseased Fleckvieh calves.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-623) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle

Jung¹,

Pausch²,

Langenmayer³

et al. 2014

BMC Genomics

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“…As summarized in the scheme presented in Fig 1A and 1B, micro-osmotic pumps were aseptically filled with either the vehicle (50% DMSO) or inhibitory compound at a concentration that would deliver 1.8 mg/kg/day of the PLD-specific inhibitors 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-naphthalenecarboxamide (VU0155072-2) ([VU0155072-2 has also been referred to as “NOPT” [31,40–42]]; at a rate of 0.11 μl/hr for 45 days (Fig 1A and 1B). There are no cytotoxic effects of 750 nM or 7.5 μM FIPI or 1 μM VU0155072-2 on DNA or protein synthesis of keratinocytes in vitro [44]. …”

Section: Resultsmentioning

confidence: 99%

PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases

2016

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Phospholipase D-2 (PLD2) has a key role in breast cancer formation and metastasis formation with PLD small inhibitors reducing primary tumor growth. This study aimed to evaluate the importance of targeting PLD on the tumor microenvironment. We provide evidence about the beneficial effect of PLD inhibitors [FIPI (dual PLD1/PLD2) or VU0155072-2 (PLD2 inhibitor)] on avoiding infiltration of tumor-helping macrophages and neutrophils. Tumor growth and metastasis within the primary tumors had low (<20% over controls) PLD enzyme activity. Unexpectedly, we found that the inhibitors also affected PLD2 gene expression and protein albeit at a lesser extent. The later could indicate that targeting both the actual PLD enzyme and its activity could be beneficial for potential cancer treatments in vivo. F4/80 and Ly6G staining of macrophages and neutrophils, respectively, and Arg1 staining data were consistent with M2 and N2 polarization. NOS2 staining increased in xenotransplants upon treatment with PLD2 inhibitors suggesting the novel observation that an increased recruitment of M1 macrophages occurred in primary tumors. PLD inhibitor-treated primary tumors had large, fragile, necrotic areas that were Arg1+ for M2 macrophages. The xenotransplants also caused the formation of large F4/80+ and Ly6G+ (>100 μm) clusters in lungs. However, PLD inhibitors, particularly FIPI, were able to diminish leukocyte presence. Ex vivo chemotaxis and PLD activity of peripheral blood neutrophils (PMN) and peritoneal macrophages was also determined. Whereas PMN had impaired functionality, macrophages did not. This significantly increased (“emboldened”) macrophage function was due to PLD inhibition. Since tumor-associated leukocytes in primary tumors and metastases were targeted via PLD inhibition, we posit that these inhibitors have a key role in cancer regression, while still affording an appropriate inflammatory response at least from off-site innate immunity macrophages.

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“…The authors proposed that the apparent diminished PG production was due to the disruption of the functional interaction of PLD2 with aquaporin-3 [67], or a previous PGdeficiency in the wounded cells. While exogenous glycerol [68] and PG [66] were shown to be able to rescue the delayed wound healing phenotype of aquaporin-3 KO mice [69], the role of PG and PLD2 in wound healing could also be linked to other PLD-derived lipids such as PA and DAG. This would be particularly interesting as it would be compatible with the DAG-rich zone observed by Vaughan et al [61].…”

Section: Dynamic Changes Of the Plasmalemma As Damage Signalsmentioning

confidence: 94%

“…production [66]. The authors proposed that the apparent diminished PG production was due to the disruption of the functional interaction of PLD2 with aquaporin-3 [67], or a previous PGdeficiency in the wounded cells.…”

Section: Dynamic Changes Of the Plasmalemma As Damage Signalsmentioning

confidence: 98%

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

Boucher

Mandato

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Wounding leads not only to plasma membrane disruption, but also to compromised cytoskeleton structures. This results not only in unwarranted exchanges between the cytosol and extracellular milieu, but also in loss of tensegrity, which may further endanger the cell. Tensegrity can be described as the interplay between the tensile forces generated by the apparent membrane tension, actomyosin contraction, and the cytoskeletal structures resisting those changes (e.g., microtubules). It is responsible for the structural integrity of the cell and for its ability to sense mechanical signals. Recent reviews dealing with single-cell healing mostly focused on the molecular machineries controlling the traffic and fusion of specific vesicles, or their role in different pathologies. In this review, we aim to take a broader view of the different modes of single cell repair, while focussing on the different ways the changes in plasmalemma surface area and composition, plasmalemma tension, and cytoskeletal dynamics may influence and affect single-cell repair.

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Cell wounding activates phospholipase D in primary mouse keratinocytes

Cited by 29 publications

References 43 publications

A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle

A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle

PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

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