Drosophila CerS homeodomain sites differentially alter insulin resistance
Abstract
Background: Ceramides are central sphingolipid intermediates whose abundance and molecular composition are closely linked to insulin resistance. Ceramide synthases (CerSs) generate ceramides and, in several family members, also contain a conserved homeodomain with poorly understood metabolic functions. Drosophila has a single CerS, Schlank, which contains a catalytic Lag1p motif and two predicted nuclear localization sequences, NLS1 and NLS2. We investigated how distinct Schlank homeodomain mutations affect high-sugar diet (HSD)-induced insulin resistance.
Results: Endogenous KINLS1 and KIE118A knock-in alleles retained DNA binding and transcriptional repression under basal conditions but increased susceptibility to HSD-induced metabolic dysfunction. Both mutants developed enhanced hyperglycemia and impaired insulin-responsive tGPH recruitment, while KIE118A additionally showed increased FoxO nuclear localization and DILP2 retention in insulin-producing cells. By contrast, fat-body-specific switching to the DNA-binding-deficient NLS2 variant or the catalytically inactive H215D variant attenuated selected HSD-induced phenotypes, including FoxO nuclear accumulation and DILP2 retention, without fully correcting hyperglycemia or reduced body weight. Lipidomic analysis revealed extensive diet-dependent sphingolipid remodeling. In particular, NLS2 and H215D markedly reduced the fat-body ceramide pool, including abundant d14:1/20:0- and d14:1/22:0-containing Cer, CerPE, and HexCer species.
Conclusions: The Schlank homeodomain regulates insulin homeostasis in a site- and tissue-dependent manner. Distinct homeodomain mutations can either increase susceptibility to or partially attenuate HSD-induced insulin resistance, potentially involving insulin signaling, inter-organ communication, and sphingolipid composition.
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BibTeX
@article{veragranda2026drosophila,
title = {{Drosophila CerS homeodomain sites differentially alter insulin resistance}},
author = {Christian Vera-Granda and Mariangela Sociale and Konstantin Beckschäfer and Ilja Kanevskij and Merlin Gerding and Franka Eckardt and Hannah Rindsfüsser and Christoph Thiele and Anna B. Ziegler and Margret H. Bülow and Reinhard Bauer},
journal = {BMC Biology},
year = {2026},
month = oct,
doi = {10.1186/s12915-026-02763-9},
url = {https://link.springer.com/article/10.1186/s12915-026-02763-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Drosophila CerS homeodomain sites differentially alter insulin resistance
AU - Christian Vera-Granda
AU - Mariangela Sociale
AU - Konstantin Beckschäfer
AU - Ilja Kanevskij
AU - Merlin Gerding
AU - Franka Eckardt
AU - Hannah Rindsfüsser
AU - Christoph Thiele
AU - Anna B. Ziegler
AU - Margret H. Bülow
AU - Reinhard Bauer
PY - 2026
DA - 2026/10/16
JO - BMC Biology
DO - 10.1186/s12915-026-02763-9
UR - https://link.springer.com/article/10.1186/s12915-026-02763-9
AB - Background: Ceramides are central sphingolipid intermediates whose abundance and molecular composition are closely linked to insulin resistance. Ceramide synthases (CerSs) generate ceramides and, in several family members, also contain a conserved homeodomain with poorly understood metabolic functions. Drosophila has a single CerS, Schlank, which contains a catalytic Lag1p motif and two predicted nuclear localization sequences, NLS1 and NLS2. We investigated how distinct Schlank homeodomain mutations affect high-sugar diet (HSD)-induced insulin resistance. Results: Endogenous KINLS1 and KIE118A knock-in alleles retained DNA binding and transcriptional repression under basal conditions but increased susceptibility to HSD-induced metabolic dysfunction. Both mutants developed enhanced hyperglycemia and impaired insulin-responsive tGPH recruitment, while KIE118A additionally showed increased FoxO nuclear localization and DILP2 retention in insulin-producing cells. By contrast, fat-body-specific switching to the DNA-binding-deficient NLS2 variant or the catalytically inactive H215D variant attenuated selected HSD-induced phenotypes, including FoxO nuclear accumulation and DILP2 retention, without fully correcting hyperglycemia or reduced body weight. Lipidomic analysis revealed extensive diet-dependent sphingolipid remodeling. In particular, NLS2 and H215D markedly reduced the fat-body ceramide pool, including abundant d14:1/20:0- and d14:1/22:0-containing Cer, CerPE, and HexCer species. Conclusions: The Schlank homeodomain regulates insulin homeostasis in a site- and tissue-dependent manner. Distinct homeodomain mutations can either increase susceptibility to or partially attenuate HSD-induced insulin resistance, potentially involving insulin signaling, inter-organ communication, and sphingolipid composition.
SN - 1741-7007
ER -