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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

Knock-down of BM-40-SPARC (BM-40-SPARC>BM-40-SPARCi) causes PM accumulation of Collagen IV without PM overgrowth.DOI:http://dx.doi.org/10.7554/eLife.07187.018
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fig8s1: Knock-down of BM-40-SPARC (BM-40-SPARC>BM-40-SPARCi) causes PM accumulation of Collagen IV without PM overgrowth.DOI:http://dx.doi.org/10.7554/eLife.07187.018

Mentions: Besides endocytic genes and cactus, our screening has found additional hits causing Collagen IV accumulation at the PM (Supplementary file 1). Loss of BM-40-SPARC, one of these hits, was previously known to cause Collagen IV deposits on adipocytes (Pastor-Pareja and Xu, 2011). Furthermore, similar to the fibrotic deposits in our study, other basement membrane components accumulate upon loss of BM-40-SPARC (Shahab et al., 2015). However, the PM is not overgrown in BM-40-SPARCi adipocytes (Figure 8—figure supplement 1), suggesting that the way in which aggregates form in BM-40-SPARCi adipocytes is different from the way they arise in endocytosis-defective and Toll-activated adipocytes. We have also tested Toll pathway activation by examining expression of Toll target Drosomycin (Drs-GFP) in BM-40-SPARCi and all other PM accumulation hits, but found no Drosomycin-GFP induction in any of them. This suggests that, cactus aside, none of the hits causes Collagen IV deposits through ectopic Toll activation. Further characterization work, therefore, is needed to ascertain the particular mechanisms by which PM accumulation of Collagen IV occurs upon loss of these genes. Such work might offer additional insights for a better understanding of fibrosis.


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)

Knock-down of BM-40-SPARC (BM-40-SPARC>BM-40-SPARCi) causes PM accumulation of Collagen IV without PM overgrowth.DOI:http://dx.doi.org/10.7554/eLife.07187.018
© Copyright Policy
Related In: Results  -  Collection

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

fig8s1: Knock-down of BM-40-SPARC (BM-40-SPARC>BM-40-SPARCi) causes PM accumulation of Collagen IV without PM overgrowth.DOI:http://dx.doi.org/10.7554/eLife.07187.018
Mentions: Besides endocytic genes and cactus, our screening has found additional hits causing Collagen IV accumulation at the PM (Supplementary file 1). Loss of BM-40-SPARC, one of these hits, was previously known to cause Collagen IV deposits on adipocytes (Pastor-Pareja and Xu, 2011). Furthermore, similar to the fibrotic deposits in our study, other basement membrane components accumulate upon loss of BM-40-SPARC (Shahab et al., 2015). However, the PM is not overgrown in BM-40-SPARCi adipocytes (Figure 8—figure supplement 1), suggesting that the way in which aggregates form in BM-40-SPARCi adipocytes is different from the way they arise in endocytosis-defective and Toll-activated adipocytes. We have also tested Toll pathway activation by examining expression of Toll target Drosomycin (Drs-GFP) in BM-40-SPARCi and all other PM accumulation hits, but found no Drosomycin-GFP induction in any of them. This suggests that, cactus aside, none of the hits causes Collagen IV deposits through ectopic Toll activation. Further characterization work, therefore, is needed to ascertain the particular mechanisms by which PM accumulation of Collagen IV occurs upon loss of these genes. Such work might offer additional insights for a better understanding of fibrosis.

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