Biology subjects

McMullen, E.

Publications and source records attributed to McMullen, E..

3 recordsLinked to original sources

bioRxiv2023

JAK/STAT mediated insulin resistance in muscles is essential for effective immune response

The metabolically demanding nature of immune response requires nutrients to be preferentially directed towards the immune system at the expense of peripheral tissues. We study the mechanisms by which this metabolic reprograming occurs using the parasitoid infection of Drosophila larvae. To overcome such an immune challenge hemocytes differentiate into lamellocytes, which encapsulate and melanize the parasitoid egg. Hemocytes acquire the energy for this process by expressing JAK/STAT ligands upd2 and upd3, which activates JAK/STAT signaling in muscles and redirects carbohydrates away from muscles in favor of immune cells. Absence of upd/JAK/STAT signaling leads to an impaired immune response and increased mortality. We demonstrate how JAK/STAT signaling in muscles leads to suppression of insulin signaling through activation of ImpL2, the inhibitor of Drosophila insulin like peptides. We reveal the crucial function of muscles during immune response and show the benefits of insulin resistance as an adaptive mechanism that is necessary for survival.

immunology↗

bioRxiv2023

Metabolism of glucose and trehalose by cyclic pentose phosphate pathway is essential for effective immune response in Drosophila

Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection of Drosophila larvae by parasitoid wasp. Neutralization of the parasitoid egg involves the differentiation of lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg; meanwhile the capsule created also protects the host from the toxic reaction. We combine transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically in Drosophila hemocytes. We found that hemocytes increase the expression of several carbohydrate transporters, and accordingly uptake of sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH production. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose, within the cell, to fuel cyclic PPP. Intracellular trehalose metabolism is not required for resistance, but may be associated with host protection from its own toxic response. Thus, our results suggest that sugar metabolism within immune cells, and specifically in cyclic PPP, may be important for not only fighting infection, but also for protecting the host from its own immune response and ensuring sufficient fitness of the survivor.

immunology↗

bioRxiv2020

Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

During hunger or malnutrition animals prioritize alimentation of the brain over other organs to ensure its function and thus their survival. This so-called brain sparing is described from Drosophila to humans. However, little is known about the molecular mechanisms adapting carbohydrate transport. Here, we used Drosophila genetics to unravel the mechanisms operating at the blood-brain barrier (BBB) under nutrient restriction. During starvation, expression of the carbohydrate transporter Tret1-1 is increased to provide more efficient carbohydrate uptake. Two mechanisms are responsible for this increase. Similarly to the regulation of mammalian GLUT4, Rab-dependent intracellular shuttling is needed for Tret1-1 integration into the plasma membrane, even though Tret1-1 regulation is independent of insulin signaling. In addition, starvation induces transcriptional upregulation controlled by TGF-{beta} signaling. Considering TGF-{beta}-dependent regulation of the glucose transporter GLUT1 in murine chondrocytes, our study reveals an evolutionarily conserved regulatory paradigm adapting the expression of sugar transporters at the BBB.

cell biology↗