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G. Subba Rao
Assistant Professor
PhD (IMTECH, Chandigarh & CDRI, Lucknow, India)
Phone: +91 80 22932297
Email: subba@mcbl.iisc.ernet.in


The main focus of research in our laboratory is to understand the role of Hermansky-Puladk Syndrome (HPS) associated protein complexes in organelle biogenesis

Biochemical reactions within cells are compartmentalized by intracellular membranes into distinct membrane-bound organelles. Each organelle is different, sequestering different sets of competing or incompatible reactions. How do cells solve this problem? Macromolecules - including proteins that make up these organelles have to be sorted among them appropriately. By delivering structural and functional components to their proper place, intracellular sorting mechanisms actually contribute to the formation of the organelles. Our lab would like to understand how this process works?
The organelles of the endocytic pathway are particularly pleiomorphic and contribute to forming many different classes of physiologically important organelles in different cell types. Among these organelles, melanosomes in melanocytes, dense granules in platelets and others belong to a class of Lysosome-related organelles (LRO) which coexist with lysosomes in their respective cell types. Interestingly, formation and function of several LRO are defective in a multisystem genetic disorder, Hermansky-Pudlak Syndrome (HPS) and it is characterized by oculocutaneous albinism, platelet deficiency and often lung fibrosis. These defects result from mutations in 15 genes in mouse and 8 genes in human which encodes five different multi-subunit protein complexes, includes BLOC (Biogenesis of Lysosome-related Organelles Complex)-1, BLOC-2, BLOC-3, AP (Adaptor Protein)-3, HOPS (Homotypic Vacuolar Protein Sorting) complex and other subunits (Fig. 1). Our lab interested in understanding the molecular mechanism of protein transport steps mediated by these complexes to melanosomes and other organelles (Fig. 2). The following specific topics represent some of the research interests of my laboratory.
1. Role of Syntaxin13 in melanosome biogenesis and HPS disease.
2. Molecular function of BLOC-1, BLOC-2 and AP-3 in organelle biogenesis.

Esteban's_HPSFiguremodif

    Melanosome transport 2007 reivew.jpg

Fig. 1. Assembly of HPS gene products into protein complexes. Gene products associated to HPS in both human and mice are depicted in red and those mutated only in rodent models are depicted in yellow. BLOC, Biogenesis of lysosome-related organelles complex; AP, adaptor protein complex and HOPS, homotypic vacuolar protein sorting complex (adopted from Di Pietro et al., 2005, Traffic, 6:525).

Fig. 2. Protein transport pathways to melanosomes. Biosynthetic transport of three melanosome cargoes, Pmel17, Tyrp1 and tyrosinase are indicated by dashed lines. All cargoes derive from the Golgi and traverse vacuolar and/or tubular elements of early endosomes either directly or through the cell surface en route to the melanosome. St II, III and IV, different melanosome stages. Steps mediated by BLOC-1, -2 and AP-3 are indicated. (adopted from Raposo, G and Marks, MS, 2007, Nat. Rev. Mol. Cell Biol., 8:786).

  • Indian Institute of Science, Bangalore, INDIA
  • Wellcome Trust–DBT India Alliance Senior Research Fellowship, Hyderabad, INDIA
  • Prof. Michael S. Marks, Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA
  • Dr. Graca Raposo, Research Director, Structure and Membrane Compartments, Institut Curie, Paris, FRANCE

 

Selected Publications:

Truschel, S.T, Simoes, S., Setty, S.R., Harper, D.C., Tenza, D., Thomas, P.C., Herman, K.E., Sackett, S.D., Cowan, D.C., Theos, A.C., Raposo, G. and Marks, M.S. (2009) ESCRT-1 function is required for Tyrp-1 transport from early endosomes to the melanosome limiting membrane. Traffic10: 1318-1336.

Setty, S.R., Tenza, D., Sviderskaya, E.V., Bennett, D.C., Raposo, G. and Marks, M.S. (2008). Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes. Nature 454: 1142-1146.

Setty, S.R., Tenza, D., Truschel, S.T., Chou, E., Sviderskaya, E.V., Theos, A.C., Lamoreux, M.L., Di Pietro, S.M., Starcevic, M., Bennett, D.C., Dell’Angelica, E.C., Raposo, G. and Marks, M.S. (2007). BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles. Mol. Biol. Cell 18: 768-780.

Di Pietro, S.M., Falcón-Pérez, J.M., Tenza, D., Setty, S.R., Marks, M.S., Raposo, G. and Dell’Angelica, E.C. (2006). BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol. Biol. Cell 17: 4027-4038.

Burd, C.G., Strochlic, T.I. and Gangi Setty, S.R. (2004). Arf-like GTPases; not so Arf-like after all. Trends Cell Biol. 14: 687-694.

Setty, S.R., Strochlic, T.I., Tong, A.H.Y., Boone, C. and Burd, C.G. (2004). Golgi targeting of ARF- like GTPase Arl3p requires its Na-acetylation and the integral membrane protein Sys1p. Nature Cell Biol. 6: 414-419.

Setty, S.R., Shin, M.E., Yoshino, A., Marks, M.S. and Burd, C.G. (2003). Golgi recruitment of GRIP domain proteins by Arf-like GTPase 1 is regulated by Arf-like GTPase 3. Curr. Biol. 13: 401-404.