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Upcoming Seminars

Emilio Hirsch, PhD - "How human are mice? The tale of PIK3C2A and phosphatidylinositol (3,4)P2 in cytokinesis"

Professor of Experimental Biology Department of Molecular Biotechnology and Health Sciences Center for Molecular Biotechnology Via Nizza 52 10126 Torino – Italy
When Mar 05, 2020
from 12:00 PM to 01:15 PM
Where Tigem, Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Abstract
Phosphoinositides (PI) have an active role in controlling the stability and remodeling of the cytoskeleton during cell division. In particular, impaired conversion of PI(4,5)P2 to PI(4)P resulting from inactivating mutations in OCRL PI 5-phosphatase causes abscission failure, which contributes to Lowe’s syndrome pathogenesis. Whether PI(4)P, generated by OCRL at the midbody, has a role in cell division, is still unknown. Here we demonstrated that fibroblasts from patients with homozygous loss-of-function mutations in PIK3C2A have impaired cytokinesis which leads to symptomatic features, including cataracts with secondary glaucoma and kidney defects, akin to oculocerebrorenal syndrome of Lowe (OCRL) patients. Mechanistically, PI3K-C2α, encoded by PIK3C2A, produced PI(3,4)P2 at the midbody plasma membrane by converting PI(4)P generated by OCRL phosphatase- and PI4KA kinase-activity. Local PI(3,4)P2 synthesis triggered the recruitment of  ESCRT-II to the midbody thus allowing proper cell division. Our work showed that the ESCRT-II subunit, VPS36, that binds PI(3)P in yeast, has acquired increased specificity for binding to PI(3,4)P2 during evolution, thus explaining a mammalian specific process controlling cytokinetic intercellular bridge cleavage. Our findings explains the molecular shift from yeast fission to an efficient midbody-driven cytokinesis in mice and humans.

Diego di Bernardo, PhD - "Tackling biological complexity one cell at the time"

Principal Investigator, Tigem and Associate Professor of Control Engineering, Department of Chemical Engineering, University of Naples "Federico II", Italy
When Mar 10, 2020
from 12:00 PM to 01:15 PM
Where Tige Vesuvius Auditorium
Contact Name
Contact Phone 08119230659
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Luk H. Vandenberghe, PhD - "Deciphering AAV, Reprogramming Pharmacology"

Grousbeck Family Chair in Gene Therapy - Associate Professor, Dept. of Ophthalmology, Harvard - Associate Member, The Broad Institute of Harvard and MIT - Director, Grousbeck Gene Therapy Center - Boston, MA, USA
When Mar 19, 2020
from 12:00 PM to 01:15 PM
Where Tigem, Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Abstract
Therapeutic gene transfer is a novel drug modality that can transform the life of patients. AAV has emerged as a powerful in vivo gene transfer vector based on a naturally occurring virus with validaton in the lab, clinic, and more recently in the marketplace. Remarkably, AAV remains poorly understood from a mechanistic level which limits our ability to engineer tropism, host response, or manufacturing properties which may limit applications. Here, we describe a novel approach to interrogate the structure-function relationship of AAV in a high-throughput manner in a way that can inform rational design of AAV in clinically relevant ways (e.g. across species barriers).

Nico Mitro, PhD - "Zc3h10 dependent control of cellular metabolism"

Associate Professor of Biochemistry, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Itlay
When Mar 24, 2020
from 12:00 PM to 01:15 PM
Where Tigem, Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Abstract
Metabolism is the set of life-sustaining reactions in organisms. Metabolic reactions are categorized as catabolic, the breaking down of metabolites to produce energy, and/or anabolic, the synthesis of compounds that consume energy. The balance between catabolism of the preferential fuel substrate and anabolism define the overall metabolism of a cell or tissue.
The long-range goal of my laboratory is to understand how metabolism is rearranged during the development of age-related diseases. In particular, we focused our attention on the role of mitochondria that represents the energy-generating hubs of the cells. Using a genome-wide functional screen, transcriptomics, proteomics and metabolomics, we identify the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. Depletion of Zc3h10 in mouse cells, or a loss‐of‐function mutation (Tyr105Cys) in humans, results in reduced respiratory capacity and impairment of mitochondrial metabolic pathways. Furthermore, human homozygotes for this Zc3h10 mutation have increased body mass index (BMI), fat mass, altered fat distribution, elevated circulating triglyceride and glucose levels. These data are further sustained by the role of Zc3h10 as a key factor during the differentiation program of mesenchymal stem cells to mature white adipocytes.
Together, these studies reveal the importance of Zc3h10 as metabolic regulator in the transition from physiology to pathophysiology such as the development of obesity and type 2 diabetes.

Ivan Dikic, MD, PhD - "Ubiquitin and Autophagy networks in Health and Disease"

Director, Institute of Biochemistry II, Goethe University Medical School, Frankfurt a. M., Germany
When Apr 07, 2020
from 12:00 PM to 01:15 PM
Where Tigem, Auditorium Vesuvius
Contact Name
Contact Phone 08119230659
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Abstract
Ubiquitination of proteins regulates a number of key cellular processes including protein degradation, endocytosis, translation, innate immunity and DNA repair. Ubiquitin is a critical cellular signal for two major cellular quality control pathways: the proteasome degradation system and autophagy-lysosome pathway. Conventional ubiquitination involves the ATP-dependent formation of amide bonds between the ubiquitin C-terminus and lysine or methionine in substrate proteins. Recently, we have shown that pathogenic Legionella pneumophila secretes enzymes that catalyze unconventional serine ubiquitination (via phosphoribose - PR) of host proteins during bacterial infection. PR-ubiquitination impairs the function of eukaryotic cells including mitophagy, DNA repair, TNF signaling and proteasomal degradation. This activity is counteracted by the action of another Legionella effector SidJ that  opposes its toxicity in yeast and mammalian cells. SidJ is a glutamylase that modifies the catalytic glutamate in the mART domain of SidEs thus blocking their ubiquitin ligase activity. SidJ is activated by binding to calmodulin (CaM) and changes in calcium concentrations regulate the glutamylation activity in vivo. The cryo-EM structure of SidJ/human apo-CaM complex revealing the architecture of this unique glutamylase. I will present novel data demonstrating that PR-deubiquitination is also counteracted by bacterial effectors named DUPs (DeUbiquitinases for PR-ubiquitination).
The endoplasmic reticulum (ER) is the largest intracellular endomembrane system enabling synthesis and transport of cellular components. Constant ER turnover is needed to meet different cellular requirements and autophagy plays an important role in this process. The ER is degraded via a selective autophagy pathway (called ER-phagy) and mediated by specific ER-resident proteins that interact with LC3. Reticulon-type proteins FAM134B and RTN3 were shown to mediate the turnover of ER sheets or tubules, respectively. Their overexpression stimulates ER fragmentation and delivery to lysosomes via the autophagy pathway. Mutations of FAM134B in humans are unable to act as ER-phagy receptors and cause sensory neurodegeneration. The major questions we are exploring at the moment deal with the action of reticulon domains in banding the membranes and the regulatory mechanisms of a family of co-receptors that assist FAM134B or RTN3 in selecting the appropriate cargoes during the ER-phagy process. Taken together, ER-phagy possesses the potential to remodel or rebalance the entire ER network and – given the physical and functional connection of ER to other organelles inside the cell – ER-phagy might also impact the function of other organelles as well. I will also discuss the importance of ER-phagy in neuropathies and infection diseases.