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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

Perlecan, like Collagen IV, originates in the fat body.(A) Schematic representation of the in vivo YFP interference strategy (iYFPi) to knock-down expression of YFP-trapped Perlecan (Trol-YFP) and ascertain its tissue of origin. Expression of a short hairpin RNA targets the YFP sequence in the YFP-trapped mRNA for degradation through RNAi. (B) Localization of Perlecan (Trol-YFP trap) in wing discs from trolCPTI-002049/Y flies. iYFPi in the fat body (BM-40-SPARC>iYFPi) eliminates expression of Trol-YFP in the wing disc and produces tissue hyperconstriction, a previously described trol loss-of-function phenotype (Pastor-Pareja and Xu, 2011). Phalloidin staining of F-actin in red to reveal disc deformation.DOI:http://dx.doi.org/10.7554/eLife.07187.011
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fig4: Perlecan, like Collagen IV, originates in the fat body.(A) Schematic representation of the in vivo YFP interference strategy (iYFPi) to knock-down expression of YFP-trapped Perlecan (Trol-YFP) and ascertain its tissue of origin. Expression of a short hairpin RNA targets the YFP sequence in the YFP-trapped mRNA for degradation through RNAi. (B) Localization of Perlecan (Trol-YFP trap) in wing discs from trolCPTI-002049/Y flies. iYFPi in the fat body (BM-40-SPARC>iYFPi) eliminates expression of Trol-YFP in the wing disc and produces tissue hyperconstriction, a previously described trol loss-of-function phenotype (Pastor-Pareja and Xu, 2011). Phalloidin staining of F-actin in red to reveal disc deformation.DOI:http://dx.doi.org/10.7554/eLife.07187.011

Mentions: We asked next whether other proteins besides Collagen IV were pericellularly trapped due to PM overgrowth. Apart from Collagen IV, the main components of basement membranes are Perlecan, Laminin and Nidogen (Yurchenco, 2011). Whereas evidence exists of significant Laminin and Nidogen production outside the fat body (Urbano et al., 2009; Zhu et al., 2012), production of Perlecan has not been studied. Through iYFPi (in vivo YFP interference, Figure 4A), we knocked down expression of Perlecan-YFP (trolCPTI-002049 [Rees et al., 2011]), a YFP-trap insertion predicted to label all Perlecan isoforms and found that Perlecan present in imaginal discs originated entirely in the fat body (Figure 4B), same as Collagen IV. Also similar to Collagen IV, Trol-YFP was pericellularly accumulated in endocytosis-defective adipocytes (Figure 5A,B). This accumulation of Trol (terribly reduced optic lobes) depended on Collagen IV, as it was suppressed by Collagen IV knock-down (Figure 5C). Through antibody staining, we confirmed Perlecan accumulation (Figure 5—figure supplement 1) and additionally observed accumulation of Nidogen, again in a Collagen-dependent manner (Figure 5D), but not Laminin (anti-LanB1 staining, not shown).10.7554/eLife.07187.011Figure 4.Perlecan, like Collagen IV, originates in the fat body.


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)

Perlecan, like Collagen IV, originates in the fat body.(A) Schematic representation of the in vivo YFP interference strategy (iYFPi) to knock-down expression of YFP-trapped Perlecan (Trol-YFP) and ascertain its tissue of origin. Expression of a short hairpin RNA targets the YFP sequence in the YFP-trapped mRNA for degradation through RNAi. (B) Localization of Perlecan (Trol-YFP trap) in wing discs from trolCPTI-002049/Y flies. iYFPi in the fat body (BM-40-SPARC>iYFPi) eliminates expression of Trol-YFP in the wing disc and produces tissue hyperconstriction, a previously described trol loss-of-function phenotype (Pastor-Pareja and Xu, 2011). Phalloidin staining of F-actin in red to reveal disc deformation.DOI:http://dx.doi.org/10.7554/eLife.07187.011
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490375&req=5

fig4: Perlecan, like Collagen IV, originates in the fat body.(A) Schematic representation of the in vivo YFP interference strategy (iYFPi) to knock-down expression of YFP-trapped Perlecan (Trol-YFP) and ascertain its tissue of origin. Expression of a short hairpin RNA targets the YFP sequence in the YFP-trapped mRNA for degradation through RNAi. (B) Localization of Perlecan (Trol-YFP trap) in wing discs from trolCPTI-002049/Y flies. iYFPi in the fat body (BM-40-SPARC>iYFPi) eliminates expression of Trol-YFP in the wing disc and produces tissue hyperconstriction, a previously described trol loss-of-function phenotype (Pastor-Pareja and Xu, 2011). Phalloidin staining of F-actin in red to reveal disc deformation.DOI:http://dx.doi.org/10.7554/eLife.07187.011
Mentions: We asked next whether other proteins besides Collagen IV were pericellularly trapped due to PM overgrowth. Apart from Collagen IV, the main components of basement membranes are Perlecan, Laminin and Nidogen (Yurchenco, 2011). Whereas evidence exists of significant Laminin and Nidogen production outside the fat body (Urbano et al., 2009; Zhu et al., 2012), production of Perlecan has not been studied. Through iYFPi (in vivo YFP interference, Figure 4A), we knocked down expression of Perlecan-YFP (trolCPTI-002049 [Rees et al., 2011]), a YFP-trap insertion predicted to label all Perlecan isoforms and found that Perlecan present in imaginal discs originated entirely in the fat body (Figure 4B), same as Collagen IV. Also similar to Collagen IV, Trol-YFP was pericellularly accumulated in endocytosis-defective adipocytes (Figure 5A,B). This accumulation of Trol (terribly reduced optic lobes) depended on Collagen IV, as it was suppressed by Collagen IV knock-down (Figure 5C). Through antibody staining, we confirmed Perlecan accumulation (Figure 5—figure supplement 1) and additionally observed accumulation of Nidogen, again in a Collagen-dependent manner (Figure 5D), but not Laminin (anti-LanB1 staining, not shown).10.7554/eLife.07187.011Figure 4.Perlecan, like Collagen IV, originates in the fat body.

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