Bio

Professional Education


  • Doctor of Philosophy, Ruprecht Karl Universitat Heidelberg (2010)
  • Diploma di Laurea, Università Degli Studi Di Palermo (2005)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Organization and Assembly of Olfactory Circuits in Drosophila Melanogaster.

Publications

Journal Articles


  • The SUMO Protease Verloren Regulates Dendrite and Axon Targeting in Olfactory Projection Neurons JOURNAL OF NEUROSCIENCE Berdnik, D., Favaloro, V., Luo, L. 2012; 32 (24): 8331-8340

    Abstract

    Sumoylation is a post-translational modification regulating numerous biological processes. Small ubiquitin-like modifier (SUMO) proteases are required for the maturation and deconjugation of SUMO proteins, thereby either promoting or reverting sumoylation to modify protein function. Here, we show a novel role for a predicted SUMO protease, Verloren (Velo), during projection neuron (PN) target selection in the Drosophila olfactory system. PNs target their dendrites to specific glomeruli within the antennal lobe (AL) and their axons stereotypically into higher brain centers. We uncovered mutations in velo that disrupt PN targeting specificity. PN dendrites that normally target to a particular dorsolateral glomerulus instead mistarget to incorrect glomeruli within the AL or to brain regions outside the AL. velo mutant axons also display defects in arborization. These phenotypes are rescued by postmitotic expression of Velo in PNs but not by a catalytic domain mutant of Velo. Two other SUMO proteases, DmUlp1 and CG12717, can partially compensate for the function of Velo in PN dendrite targeting. Additionally, mutations in SUMO and lesswright (which encodes a SUMO conjugating enzyme) similarly disrupt PN targeting, confirming that sumoylation is required for neuronal target selection. Finally, genetic interaction studies suggest that Velo acts in SUMO deconjugation rather than in maturation. Our study provides the first in vivo evidence for a specific role of a SUMO protease during neuronal target selection that can be dissociated from its functions in neuronal proliferation and survival.

    View details for DOI 10.1523/JNEUROSCI.6574-10.2012

    View details for Web of Science ID 000305295600024

    View details for PubMedID 22699913

  • Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice NATURE Mosca, T. J., Hong, W., Dani, V. S., Favaloro, V., Luo, L. 2012; 484 (7393): 237-U122

    Abstract

    Synapse assembly requires trans-synaptic signals between the pre- and postsynapse, but our understanding of the essential organizational molecules involved in this process remains incomplete. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with ?-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection.

    View details for DOI 10.1038/nature10923

    View details for Web of Science ID 000303149900034

    View details for PubMedID 22426000

  • EBV Protein BNLF2a Exploits Host Tail-Anchored Protein Integration Machinery To Inhibit TAP JOURNAL OF IMMUNOLOGY Horst, D., Favaloro, V., Vilardi, F., van Leeuwen, H. C., Garstka, M. A., Hislop, A. D., Rabu, C., Kremmer, E., Rickinson, A. B., High, S., Dobberstein, B., Ressing, M. E., Wiertz, E. J. 2011; 186 (6): 3594-3605

    Abstract

    EBV, the prototypic human ?(1)-herpesvirus, persists for life in infected individuals, despite the presence of vigorous antiviral immunity. CTLs play an important role in the protection against viral infections, which they detect through recognition of virus-encoded peptides presented in the context of HLA class I molecules at the cell surface. The viral peptides are generated in the cytosol and are transported into the endoplasmic reticulum (ER) by TAP. The EBV-encoded lytic-phase protein BNLF2a acts as a powerful inhibitor of TAP. Consequently, loading of antigenic peptides onto HLA class I molecules is hampered, and recognition of BNLF2a-expressing cells by cytotoxic T cells is avoided. In this study, we characterize BNLF2a as a tail-anchored (TA) protein and elucidate its mode of action. Its hydrophilic N-terminal domain is located in the cytosol, whereas its hydrophobic C-terminal domain is inserted into membranes posttranslationally. TAP has no role in membrane insertion of BNLF2a. Instead, Asna1 (also named TRC40), a cellular protein involved in posttranslational membrane insertion of TA proteins, is responsible for integration of BNLF2a into the ER membrane. Asna1 is thereby required for efficient BNLF2a-mediated HLA class I downregulation. To optimally accomplish immune evasion, BNLF2a is composed of two specialized domains: its C-terminal tail anchor ensures membrane integration and ER retention, whereas its cytosolic N terminus accomplishes inhibition of TAP function. These results illustrate how EBV exploits a cellular pathway for TA protein biogenesis to achieve immune evasion, and they highlight the exquisite adaptation of this virus to its host.

    View details for DOI 10.4049/jimmunol.1002656

    View details for Web of Science ID 000287923500035

    View details for PubMedID 21296983

  • Asna1/TRC40-mediated membrane insertion of tail-anchored proteins JOURNAL OF CELL SCIENCE Favaloro, V., Vilardi, F., Schlecht, R., Mayer, M. P., Dobberstein, B. 2010; 123 (9): 1522-1530

    Abstract

    Tail-anchored (TA) proteins insert post-translationally into the membrane of the endoplasmic reticulum (ER) and span the membrane by their C-terminal transmembrane domain. We have reconstituted membrane insertion of TA proteins from recombinant Asna1/TA protein complexes and ER-derived membranes. Our data show that Asna1 can mediate membrane insertion of RAMP4 and Sec61beta without the participation of other cytosolic proteins by a mechanism that depends on the presence of ATP or ADP and a protease-sensitive receptor in the ER membrane. By contrast, membrane insertion of cytochrome b5 can proceed independently of Asna1 and nucleotides.

    View details for DOI 10.1242/jcs.055970

    View details for Web of Science ID 000276912300016

    View details for PubMedID 20375064

  • Structural insights into tail-anchored protein binding and membrane insertion by Get3 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bozkurt, G., Stjepanovic, G., Vilardi, F., Amlacher, S., Wild, K., Bange, G., Favaloro, V., Rippe, K., Hurt, E., Dobberstein, B., Sinning, I. 2009; 106 (50): 21131-21136

    Abstract

    Tail-anchored (TA) membrane proteins are involved in a variety of important cellular functions, including membrane fusion, protein translocation, and apoptosis. The ATPase Get3 (Asna1, TRC40) was identified recently as the endoplasmic reticulum targeting factor of TA proteins. Get3 consists of an ATPase and alpha-helical subdomain enriched in methionine and glycine residues. We present structural and biochemical analyses of Get3 alone as well as in complex with a TA protein, ribosome-associated membrane protein 4 (Ramp4). The ATPase domains form an extensive dimer interface that encloses 2 nucleotides in a head-to-head orientation and a zinc ion. Amide proton exchange mass spectrometry shows that the alpha-helical subdomain of Get3 displays considerable flexibility in solution and maps the TA protein-binding site to the alpha-helical subdomain. The non-hydrolyzable ATP analogue AMPPNP-Mg(2+)- and ADP-Mg(2+)-bound crystal structures representing the pre- and posthydrolysis states are both in a closed form. In the absence of a TA protein cargo, ATP hydrolysis does not seem to be possible. Comparison with the ADP.AlF(4)(-)-bound structure representing the transition state (Mateja A, et al. (2009) Nature 461:361-366) indicates how the presence of a TA protein is communicated to the ATP-binding site. In vitro membrane insertion studies show that recombinant Get3 inserts Ramp4 in a nucleotide- and receptor-dependent manner. Although ATP hydrolysis is not required for Ramp4 insertion per se, it seems to be required for efficient insertion. We postulate that ATP hydrolysis is needed to release Get3 from its receptor. Taken together, our results provide mechanistic insights into posttranslational targeting of TA membrane proteins by Get3.

    View details for DOI 10.1073/pnas.0910223106

    View details for Web of Science ID 000272795300024

    View details for PubMedID 19948960

  • Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins JOURNAL OF CELL SCIENCE Favaloro, V., Spasic, M., Schwappach, B., Dobberstein, B. 2008; 121 (11): 1832-1840

    Abstract

    Tail-anchored (TA) proteins are characterised by a C-terminal transmembrane region that mediates post-translational insertion into the membrane of the endoplasmic reticulum (ER). We have investigated the requirements for membrane insertion of three TA proteins, RAMP4, Sec61beta and cytocrome b5. We show here that newly synthesised RAMP4 and Sec61beta can accumulate in a cytosolic, soluble complex with the ATPase Asna1 before insertion into ER-derived membranes. Membrane insertion of these TA proteins is stimulated by ATP, sensitive to redox conditions and blocked by alkylation of SH groups by N-ethylmaleimide (NEM). By contrast, membrane insertion of cytochrome b5 is not found to be mediated by Asna1, not stimulated by ATP and not affected by NEM or an oxidative environment. The Asna1-mediated pathway of membrane insertion of RAMP4 and Sec61beta may relate to functions of these proteins in the ER stress response.

    View details for DOI 10.1242/jcs.020321

    View details for Web of Science ID 000256069500008

    View details for PubMedID 18477612

  • Thyroid hormones induce sumoylation of the cold shock domain-containing protein PIPPin in developing rat brain and in cultured neurons ENDOCRINOLOGY Bono, E., Compagno, V., Proia, P., Raimondi, L., Schiera, G., Favaloro, V., Campo, V., Donatelli, M., Di Liegro, I. 2007; 148 (1): 252-257

    Abstract

    We previously identified a cold shock domain (CSD)-containing protein (PIPPin), expressed at high level in brain cells. PIPPin has the potential to undergo different posttranslational modifications and might be a good candidate to regulate the synthesis of specific proteins in response to extracellular stimuli. Here we report the effects of T(3) on PIPPin expression in developing rat brain. We found that a significant difference among euthyroid and hypothyroid newborn rats concerns sumoylation of nuclear PIPPin, which is abolished by hypothyroidism. Moreover, T(3) dependence of PIPPin sumoylation has been confirmed in cortical neurons purified from brain cortices and cultured in a chemically defined medium (Maat medium), with or without T(3). We also report that about one half of unmodified as well as all the sumoylated form of PIPPin could be extracted from nuclei with HCl, together with histones. Moreover, this HCl-soluble fraction remains in the nucleus even after treatment with 0.6 M KCl, thus suggesting strong interaction of PIPPin with nuclear structures and perhaps chromatin.

    View details for DOI 10.1210/en.2006-0660

    View details for Web of Science ID 000242935200029

    View details for PubMedID 17053029

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