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Plasma membrane overgrowth causes fibrotic collagen accumulation and immune activation in Drosophila adipocytes.

Zang Y, Wan M, Liu M, Ke H, Ma S, Liu LP, Ni JQ, Pastor-Pareja JC - Elife (2015)

Bottom Line: Deposits also form in the absence of negative Toll immune regulator Cactus, excess PM being caused in this case by increased secretion.Finally, we show that trimeric Collagen accumulation, downstream of Toll or endocytic defects, activates a tissue damage response.It also places fibrotic deposits both downstream and upstream of immune signaling, consistent with the chronic character of fibrotic diseases.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Tsinghua University, Beijing, China.

ABSTRACT
Many chronic diseases are associated with fibrotic deposition of Collagen and other matrix proteins. Little is known about the factors that determine preferential onset of fibrosis in particular tissues. Here we show that plasma membrane (PM) overgrowth causes pericellular Collagen accumulation in Drosophila adipocytes. We found that loss of Dynamin and other endocytic components causes pericellular trapping of outgoing Collagen IV due to dramatic cortex expansion when endocytic removal of PM is prevented. Deposits also form in the absence of negative Toll immune regulator Cactus, excess PM being caused in this case by increased secretion. Finally, we show that trimeric Collagen accumulation, downstream of Toll or endocytic defects, activates a tissue damage response. Our work indicates that traffic imbalances and PM topology may contribute to fibrosis. It also places fibrotic deposits both downstream and upstream of immune signaling, consistent with the chronic character of fibrotic diseases.

No MeSH data available.


Related in: MedlinePlus

(A) Confocal images of fat body dissected from first, second and third instar larvae.myr-RFP membrane marker in white. PM convolution is apparent in third instar larvae. (B) Confocal (BODIPY staining) and electron micrographs showing surface lipid droplets (arrows) surrounded by PM in larva 3 adipocytes. (C) Electron micrographs of the PM of adipocytes from control w1118, BM-40-SPARC>shii, >Chci and >Rab5i third instar fat body. Intracellular volume indicated with a transparent yellow layer in right panels. Pericellular deposits of extracellular material marked by asterisks. (D) Electron micrographs of the PM of adipocytes from larvae grown in lipid-depleted medium.DOI:http://dx.doi.org/10.7554/eLife.07187.009
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fig3s1: (A) Confocal images of fat body dissected from first, second and third instar larvae.myr-RFP membrane marker in white. PM convolution is apparent in third instar larvae. (B) Confocal (BODIPY staining) and electron micrographs showing surface lipid droplets (arrows) surrounded by PM in larva 3 adipocytes. (C) Electron micrographs of the PM of adipocytes from control w1118, BM-40-SPARC>shii, >Chci and >Rab5i third instar fat body. Intracellular volume indicated with a transparent yellow layer in right panels. Pericellular deposits of extracellular material marked by asterisks. (D) Electron micrographs of the PM of adipocytes from larvae grown in lipid-depleted medium.DOI:http://dx.doi.org/10.7554/eLife.07187.009

Mentions: To characterize in further detail the topology of the PM at the site of Collagen accumulation, we analyzed confocal and electron micrographs. Wild type adipocyte PM, which is flat during the first and second larval instars, becomes somewhat convoluted in the third instar (Figure 3—figure supplement 1), displaying multiple invaginations which often encircle surface lipid droplets (Diaconeasa et al., 2013). Compared to this, examination of endocytosis-deficient adipocytes revealed a striking increase in PM amount with respect to the wild type (Figure 3A,B). Quantification in both confocal and electron micrographs showed an increase in the depth of PM ingression into the cytoplasm and higher PM sinuosity in endocytosis-defective cells (Figure 3C; Figure 3—figure supplement 2). The opposite phenotype, PM flattening, along with a vesicle-filled cytoplasm, resulted from Rab11 knock down. These results indicate that both endocytosis and membrane recycling are critical to maintain normal PM amount and cortical morphology, suggesting that Collagen IV is trapped in an abnormally expanded cell cortex when endocytic removal of membrane from the PM is prevented.10.7554/eLife.07187.008Figure 3.Pericellular Collagen trapping is due to PM overgrowth.


Plasma membrane overgrowth causes fibrotic collagen accumulation and immune activation in Drosophila adipocytes.

Zang Y, Wan M, Liu M, Ke H, Ma S, Liu LP, Ni JQ, Pastor-Pareja JC - Elife (2015)

(A) Confocal images of fat body dissected from first, second and third instar larvae.myr-RFP membrane marker in white. PM convolution is apparent in third instar larvae. (B) Confocal (BODIPY staining) and electron micrographs showing surface lipid droplets (arrows) surrounded by PM in larva 3 adipocytes. (C) Electron micrographs of the PM of adipocytes from control w1118, BM-40-SPARC>shii, >Chci and >Rab5i third instar fat body. Intracellular volume indicated with a transparent yellow layer in right panels. Pericellular deposits of extracellular material marked by asterisks. (D) Electron micrographs of the PM of adipocytes from larvae grown in lipid-depleted medium.DOI:http://dx.doi.org/10.7554/eLife.07187.009
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4490375&req=5

fig3s1: (A) Confocal images of fat body dissected from first, second and third instar larvae.myr-RFP membrane marker in white. PM convolution is apparent in third instar larvae. (B) Confocal (BODIPY staining) and electron micrographs showing surface lipid droplets (arrows) surrounded by PM in larva 3 adipocytes. (C) Electron micrographs of the PM of adipocytes from control w1118, BM-40-SPARC>shii, >Chci and >Rab5i third instar fat body. Intracellular volume indicated with a transparent yellow layer in right panels. Pericellular deposits of extracellular material marked by asterisks. (D) Electron micrographs of the PM of adipocytes from larvae grown in lipid-depleted medium.DOI:http://dx.doi.org/10.7554/eLife.07187.009
Mentions: To characterize in further detail the topology of the PM at the site of Collagen accumulation, we analyzed confocal and electron micrographs. Wild type adipocyte PM, which is flat during the first and second larval instars, becomes somewhat convoluted in the third instar (Figure 3—figure supplement 1), displaying multiple invaginations which often encircle surface lipid droplets (Diaconeasa et al., 2013). Compared to this, examination of endocytosis-deficient adipocytes revealed a striking increase in PM amount with respect to the wild type (Figure 3A,B). Quantification in both confocal and electron micrographs showed an increase in the depth of PM ingression into the cytoplasm and higher PM sinuosity in endocytosis-defective cells (Figure 3C; Figure 3—figure supplement 2). The opposite phenotype, PM flattening, along with a vesicle-filled cytoplasm, resulted from Rab11 knock down. These results indicate that both endocytosis and membrane recycling are critical to maintain normal PM amount and cortical morphology, suggesting that Collagen IV is trapped in an abnormally expanded cell cortex when endocytic removal of membrane from the PM is prevented.10.7554/eLife.07187.008Figure 3.Pericellular Collagen trapping is due to PM overgrowth.

Bottom Line: Deposits also form in the absence of negative Toll immune regulator Cactus, excess PM being caused in this case by increased secretion.Finally, we show that trimeric Collagen accumulation, downstream of Toll or endocytic defects, activates a tissue damage response.It also places fibrotic deposits both downstream and upstream of immune signaling, consistent with the chronic character of fibrotic diseases.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Tsinghua University, Beijing, China.

ABSTRACT
Many chronic diseases are associated with fibrotic deposition of Collagen and other matrix proteins. Little is known about the factors that determine preferential onset of fibrosis in particular tissues. Here we show that plasma membrane (PM) overgrowth causes pericellular Collagen accumulation in Drosophila adipocytes. We found that loss of Dynamin and other endocytic components causes pericellular trapping of outgoing Collagen IV due to dramatic cortex expansion when endocytic removal of PM is prevented. Deposits also form in the absence of negative Toll immune regulator Cactus, excess PM being caused in this case by increased secretion. Finally, we show that trimeric Collagen accumulation, downstream of Toll or endocytic defects, activates a tissue damage response. Our work indicates that traffic imbalances and PM topology may contribute to fibrosis. It also places fibrotic deposits both downstream and upstream of immune signaling, consistent with the chronic character of fibrotic diseases.

No MeSH data available.


Related in: MedlinePlus