Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Hallier, Benjamin; Schiemann, Ronja; Cordes, Eva; Vitos-Faleato, Jessica; Walter, Stefan; Heinisch, Jürgen J.; Malmendal, Anders; Paululat, Achim; Meyer, Heiko

doi:10.7554/elife.19430

Cited by 23 publications

(23 citation statements)

References 57 publications

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“…The unique role of muscles in this context was unexpected, but is probably due to the fact that muscles provide the main reservoir for stored glycogen which supplies energy required for larvae to hatch, feed, and crawl 43 , 44 , 70 . Muscle-specific expression of the insulin-processing enzyme neprilysin 4 was recently found to control insulin-like peptide abundance and food intake 71 , giving further support for the role of muscles in the systemic control of the nutrient balance. Similarly, in a recently published paper 72 , Zhao and Karpac show how signals from skeletal muscles control nutrient storage in adult Drosophila .…”

Section: Discussionmentioning

confidence: 84%

Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism

Yang

Hultmark

2017

Sci Rep

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We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles. Specifically, stimulation of JAK/STAT signaling in the muscles can rescue the deficient immune response when insulin signaling is suppressed. Our results shed new light on the interaction between metabolism, immunity, and tissue communication.

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Section: Discussionmentioning

confidence: 84%

Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism

Yang

Hultmark

2017

Sci Rep

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“…Cell culture and transfection was performed as described in ( Hallier et al, 2016 ). For heterologous expression in H5 cells, full-length Prc was cloned into the pFastBacDual vector (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

Biosynthesis and assembly of the Collagen IV-like protein Pericardin inDrosophila melanogaster

et al. 2018

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In Drosophila, formation of the cardiac extracellular matrix (ECM) starts during embryogenesis. Assembly and incorporation of structural proteins such as Collagen IV, Pericardin, and Laminin A, B1, and B2 into the cardiac ECM is critical to the maintenance of heart integrity and functionality and, therefore, to longevity of the animal. The cardiac ECM connects the heart tube with the alary muscles; thus, the ECM contributes to a flexible positioning of the heart within the animal's body. Moreover, the cardiac ECM holds the larval pericardial nephrocytes in close proximity to the heart tube and the inflow tract, which is assumed to be critical to efficient haemolymph clearance. Mutations in either structural ECM constituents or ECM receptors cause breakdown of the ECM network upon ageing, with disconnection of the heart tube from alary muscles becoming apparent at larval stages. Finally, the heart becomes non-functional. Here, we characterised existing and new pericardin mutants and investigated biosynthesis, secretion, and assembly of Pericardin in matrices. We identified two new pericardin alleles, which turned out to be a null (pericardin3-548) and a hypomorphic allele (pericardin3-21). Both mutants could be rescued with a genomic duplication of a fosmid coding for the pericardin locus. Biochemical analysis revealed that Pericardin is highly glycosylated and forms redox-dependent multimers. Multimer formation is remarkably reduced in animals deficient for the prolyl-4 hydroxylase cluster at 75D3-4.

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“…The respective vector (pJJH1460) was constructed similarly to the vectors described previously (31). Expression was induced as described previously (32). To track transfection efficiency, an eGFP reporter gene was inserted into the same vector under control of the p10 promoter.…”

Section: Sf21 Expression Constructs and Cell Culturementioning

confidence: 99%

Distinct domains in the matricellular protein Lonely heart are crucial for cardiac extracellular matrix formation and heart function in Drosophila

Rotstein¹,

Post²,

Reinhardt³

et al. 2018

Journal of Biological Chemistry

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The biomechanical properties of extracellular matrices (ECMs) are critical to many biological processes, including cell-cell communication and cell migration and function. The correct balance between stiffness and elasticity is essential to the function of numerous tissues, including blood vessels and the lymphatic system, and depends on ECM constituents (the "matrisome") and on their level of interconnection. However, despite its physiological relevance, the matrisome composition and organization remain poorly understood. Previously, we reported that the ADAMTS-like protein Lonely heart (Loh) is critical for recruiting the type IV collagen-like protein Pericardin to the cardiac ECM. Here, we utilized as a simple and genetically amenable invertebrate model for studying Loh-mediated recruitment of tissue-specific ECM components such as Pericardin to the ECM. We focused on the functional relevance of distinct Loh domains to protein localization and Pericardin recruitment. Analysis of Loh deletion constructs revealed that one thrombospondin type 1 repeat (TSR1-1), which has an embedded WW motif, is critical for anchoring Loh to the ECM. Two other thrombospondin repeats, TSR1-2 and TSR1-4, the latter containing a CTCG motif, appeared to be dispensable for tethering Loh to the ECM but were crucial for proper interaction with and recruitment of Pericardin. Moreover, our results also suggested that Pericardin in the cardiac ECM primarily ensures the structural integrity of the heart, rather than increasing tissue flexibility. In conclusion, our work provides new insights into the roles of thrombospondin type 1 repeats and advances our understanding of cardiac ECM assembly and function.

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Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

Cited by 23 publications

References 57 publications

Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism

Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism

Biosynthesis and assembly of the Collagen IV-like protein Pericardin inDrosophila melanogaster

Distinct domains in the matricellular protein Lonely heart are crucial for cardiac extracellular matrix formation and heart function in Drosophila

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