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

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.

DOI: http://dx.doi.org/10.7554/eLife.07187.001

eLife digest

In animals, so-called ‘basement membranes’ surround organs and help to both anchor certain tissue types together and control which molecules move between them. The basement membrane is made up of various proteins, and a large protein called Collagen IV is the most abundant component.

Collagen IV is made inside cells and packaged into bubble-like compartments called vesicles. These vesicles then merge with the cell membrane, which releases the collagen into the space outside the cell. Sometimes, after it has been released from the cell, Collagen IV forms harmful aggregates that the body finds difficult to break down. This condition is known as fibrosis, and can severely damage organs and tissues.

Zang, Wan et al. have now studied how fat cells—also known as adipocytes—in the fruit fly Drosophila melanogaster release Collagen IV. This fly is widely used to study collagen production because it is relatively easy to perform genetic investigations on it, and it releases collagen from its cells in the same way as many other species. Unexpectedly, it was observed that proteins that control a process known as endocytosis—which takes substances into the cell—are also involved in releasing Collagen IV from the cell. Zang, Wan et al. found that this is because endocytosis removes part of the cell membrane: if endocytosis is blocked, then the excess cell membrane traps Collagen IV molecules after they have been released, causing aggregates like those seen during fibrosis. However, artificially decreasing the amount of cell membrane restored normal collagen release.

Zang, Wan et al. next found that a pathway called Toll, which is important for protecting flies against infections, can also affect collagen release. When a protein that inactivates the Toll pathway is absent, too much cell membrane grows and Collagen IV forms aggregates as well. In both cases, Toll activation or lack of endocytosis, the aggregates trigger a reaction that damages the adipocytes. Understanding this reaction in more detail could help to develop treatments for conditions that produce fibrosis.

DOI: http://dx.doi.org/10.7554/eLife.07187.002