Biology subjects

Lillo, C.

Publications and source records attributed to Lillo, C..

3 recordsLinked to original sources

bioRxiv2023

Identification of novel interactors of PP2A-B'ζ

Protein phosphatase 2A (PP2A) is a heterotrimeric conserved serine/threonine phosphatase complex including a catalytic, scaffolding, and regulatory subunit. Three A Subunits, 17 B subunits, and five C subunits are encoded by the Arabidopsis genome, allowing 255 possible PP2A holoenzyme combinations. The regulatory subunits are crucial for substrate specificity and PP2A complex localization and are classified into B, B, and B non-related families in land plants. In Arabidopsis, the close homologs B{eta}, B{theta}, B{gamma}, and B{zeta} are further classified into a subfamily of B called B{eta}. Previous studies suggest a role of mitochondrial targeted PP2A subunit (B{zeta}) in energy metabolism and plant innate immunity. Potentially, the PP2A-B{zeta} holoenzyme is involved in the regulation of the mitochondrial succinate/fumarate translocator or affects enzymes involved in energy metabolism. To investigate this hypothesis, the interaction between PP2A-B{zeta} and enzymes involved in the mitochondrial energy flow was investigated using bimolecular fluorescence complementation in tobacco and onion cells. Interaction of B{zeta} subunit was confirmed with the Krebs cycle proteins Succinate/fumarate translocator (mSFC1), Malate dehydrogenase (mMDH2), and Aconitase (ACO3). Additional putative interacting candidates were deduced from comparing the enriched phosphoproteomes of wild type and B{zeta} mutants: the mitochondrial regulator Arabidopsis pentatricopeptide repeat 6 (PPR6) and the two metabolic enzymes Phosphoenolpyruvate carboxylase (PPC3) and Phosphoenolpyruvate carboxykinase (PCK1). Overall, this study identifies potential PP2A substrates and highlights the role of PP2A in regulating energy metabolism in mitochondria.

plant biology↗

bioRxiv2020

Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell axons in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings support the therapeutic potential of proinsulin in RP.

neuroscience↗

bioRxiv2019

TAT-Cx43266-283 impairs metabolic plasticity in glioma stem cells in vitro and in vivo

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6 via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8-10, we investigated the effect of TAT-Cx43266-283 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283 showed decreased levels of important targets for cancer therapy, such as HK-211, 12 and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

cancer biology↗