Genetics and cell biology
Organelle biogenesis and motility
Mammalian cells contain a specific repertoire of membrane-bound organelles that are essential for their survival and role within the organism. The biogenesis, motility, signaling and intracellular connections of these organelles is required for their proper function and, when altered, can result in a variety of human diseases.
Research activity
The group investigates the mechanisms underlying these processes by focusing on the molecular pathogenesis of ocular albinism type 1, a genetic disorder characterized by visual impairment and by abnormalities of melanosomes, a special type of lysosome-related organelles, devoted to the synthesis and transport of melanin in pigment cells. In fact, loss-of-function of the ocular albinism gene OA1, encoding a unique G protein-coupled receptor localized to melanosomes, results in aberrant size, number and distribution of the organelles. Recent findings of this Unit indicate that the proper biogenesis of melanosomes requires both tight juxtaposition with mitochondria, through fibrillar bridges resembling the protein tethers linking mitochondria and endoplasmic reticulum, and dedicated transcriptional programs, regulated by the microphthalmia family of transcription factors.
A second line of research in the lab is focused on the cellular adaptations to nutrient restriction, including long-term epigenetic and transcriptional modifications. To this aim, the group is investigating the sensing and signaling pathways induced by amino acid deprivation and leading to epigenetic/transcriptional effects, by taking advantage of our previous observation that prolonged deprivation of essential amino acids causes selective and reversible reactivation of stably integrated and silenced transcriptional units of the genome, such as exogenous transgenes and HIV provirus.
Daniele T and Schiaffino MV. Lipid transfer and metabolism across the endolysosomal-mitochondrial boundary. Biochim Biophys Acta. 2016 Aug;1861(8 Pt B):880-894.
Daniele T, Hurbain I, Vago R, Casari G, Raposo G, Tacchetti C and Schiaffino MV. Mitochondria and melanosomes establish physical contacts modulated by Mfn2 and involved in organelle biogenesis. Current Biology 2014 Feb 17;24(4):393-403.
Burgoyne T, Jolly R, Martin-Martin B, Seabra MC, Piccirillo R, Schiaffino MV, Futter CE. Expression of OA1 limits the fusion of a subset of MVBs with lysosomes; a mechanism likely involved in the initial biogenesis of melanosomes. Journal of Cell Science 2013 Nov 15;126(Pt 22):5143-52.
Palmisano I, Della Chiara G, D'Ambrosio RL, Huichalaf C, Brambilla P, Corbetta S, Riba M, Piccirillo R, Valente S, Casari G, Mai A, Boneschi FM, Gabellini D, Poli G, Schiaffino MV. Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4). Proc Natl Acad Sci U S A, 2012 Aug;109 (34) E2284-E2293.
Sitaram A, Piccirillo R, Palmisano I, Harper DC, Dell’Angelica EC, Schiaffino MV and Marks MS. Localization to mature melanosomes by virtue of cytoplasmic dileucine motifs is required for human OCA2 function. Molecular Biology of the Cell 2009 Mar;20(5):1464-77.
Palmisano I, Bagnato P, Palmigiano A, Innamorati G, Rotondo G, Altimare D, Venturi C, Sviderskaya EV, Piccirillo R, Coppola M, Marigo V, Incerti B, Ballabio A, Surace EM, Tacchetti C, Bennett DC, Schiaffino MV. The ocular albinism type 1 (OA1) protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells. Human Molecular Genetics 2008 Nov 15;17(22):3487-501
Piccirillo R, Palmisano I, Innamorati G, Bagnato P, Altimare D and Schiaffino MV. An unconventional dileucine-based motif and a novel cytosolic motif are required for the lysosomal and melanosomal targeting of OA1. Journal of Cell Science 2006 May 15;119(Pt 10):2003-14.
Innamorati G, Piccirillo R, Bagnato P, Palmisano I and Schiaffino MV. The melanosomal/lysosomal protein OA1 has properties of a G protein- coupled receptor. Pigment Cell Research 2006 May 15;119(Pt 10):2003-14.
Schiaffino MV, Dellambra E, Cortese K, Baschirotto C, Bondanza S, Clementi M, Nucci P, Ballabio A, Tacchetti C and De Luca M. Effective retroviral-mediated gene transfer in normal and mutant human melanocytes. Human Gene Therapy 2002 May 20;13(8):947-57.
Schiaffino MV, d’Addio M, Alloni A, Baschirotto C, Valetti C, Cortese K, Puri C. Bassi MT, Colla C, De Luca M, Tacchetti C and Ballabio A. Ocular Albinism: evidence for a defect in an intracellular signal transduction system. Nature Genetics 1999 Sep;23(1):108-12.
