Biology subjects

Cervenka, I.

Publications and source records attributed to Cervenka, I..

4 recordsLinked to original sources

bioRxiv2023

A new mechanism of posttranslational polyglutamylation regulates phase separation and signaling of the Wnt pathway protein Dishevelled.

Polyglutamylation is a reversible post-translational modification that is catalyzed by enzymes from the tubulin tyrosine ligase-like (TTLL) family. Here, we found that TTLL11 generates a previously unknown type of polyglutamylation initiated by the addition of a glutamate residue to the free C-terminal carboxyl group of a substrate protein. TTLL11 efficiently polyglutamylates the Wnt signaling protein Disheveled 3 (DVL3), thereby changing the interactome of DVL3, as well as it increases its capacity to get phosphorylated, to undergo liquid-liquid phase separation (LLPS), and to act in the non-canonical Wnt pathway. Both carboxyterminal polyglutamylation and the resulting reduction in LLPS capacity of DVL3 were reverted by the deglutamylating enzyme CCP6, which demonstrates the causal relationship between TTLL11-mediated polyglutamylation and LLPS. We thus discovered a novel type of posttranslational modification, which significantly broadens the range of proteins that can be modified by polyglutamylation and provides the first evidence that polyglutamylation can act as a regulator of protein LLPS.

cell biology↗

bioRxiv2023

Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and regeneration.

Muscular atrophy is a mortality risk factor that happens with disuse, chronic disease, and aging. Recovery from atrophy requires changes in several cell types including muscle fibers, and satellite and immune cells. Here we show that Zfp697/ZNF697 is a damage-induced regulator of muscle regeneration, during which its expression is transiently elevated. Conversely, sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Myofiber-specific Zfp697 ablation hinders the inflammatory and regenerative response to muscle injury, compromising functional recovery. We uncover Zfp697 as an essential interferon gamma mediator in muscle cells, interacting primarily with ncRNAs such as the pro-regenerative miR-206. In sum, we identify Zfp697 as an integrator of cell-cell communication necessary for tissue regeneration. One Sentence SummaryZfp697 is necessary for interferon gamma signaling and muscle regeneration.

physiology↗

bioRxiv2022

Protection from liver cancer in a mouse model of Alagille syndrome follows dysregulated differentiation of thymocytes and hepatocytes

Fibrosis is a physiological tissue repair mechanism, but excessive fibrosis can disrupt organ function. Alagille syndrome (ALGS), which is caused by mutations in the Notch ligand JAGGED1, results in bile duct paucity, neonatal cholestasis, and a characteristic fibrotic response. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulates ALGS-like pericellular fibrosis. Single-cell RNA-seq and multi-color flow cytometry characterization of the liver and spleen revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration in cholestatic Jag1Ndr/Ndr mice, despite an enrichment in extrahepatic (thymic and splenic) regulatory T cells (Tregs). Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive immune cell transplantation into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes, in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, we show that the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation are corroborated by transcriptomic data from children with ALGS. In sum, these data lead to a model in which Jag1-driven developmental hepatic and immune defects interact to determine the fibrotic process in ALGS.

developmental biology↗

bioRxiv2021

Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity.

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA-sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift towards a slow MN identity. In muscle, NRTN increased capillary density, oxidative capacity, and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs, makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-11. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity. HIGHLIGHTSO_LINRTN is a myokine induced by physical exercise. C_LIO_LIMuscle-derived NRTN promotes a slow motor neuron identity. C_LIO_LIMuscle-derived NRTN enhances muscle oxidative metabolism. C_LIO_LINRTN improves systemic metabolism, exercise performance and motor coordination. C_LI

physiology↗