@article {706, title = {Dynein Clusters into Lipid Microdomains on Phagosomes to Drive Rapid Transport toward Lysosomes.}, journal = {Cell}, volume = {164}, year = {2016}, month = {2016 Feb 11}, pages = {722-34}, abstract = {

Diverse cellular processes are driven by motor proteins that are recruited to and generate force on lipid membranes. Surprisingly little is known about how membranes control the force from motors and how this may impact specific cellular functions. Here, we show that dynein motors physically cluster into microdomains on the membrane of a phagosome as it matures inside cells. Such geometrical reorganization allows many dyneins within a cluster to generate cooperative force on a single microtubule. This results in rapid directed transport of the phagosome toward microtubule minus ends, likely promoting phagolysosome fusion and pathogen degradation. We show that lipophosphoglycan, the major molecule implicated in immune evasion of Leishmania donovani, inhibits phagosome motion by disrupting the clustering and therefore the cooperative force generation of dynein. These findings appear relevant to several pathogens that prevent phagosome-lysosome fusion by targeting lipid microdomains on phagosomes.

}, keywords = {Animals, Biological Transport, Cell Line, Dictyostelium, Dyneins, Glycosphingolipids, Leishmania donovani, Lysosomes, Membrane Microdomains, Mice, Phagosomes}, issn = {1097-4172}, doi = {10.1016/j.cell.2015.12.054}, author = {Rai, Ashim and Pathak, Divya and Thakur, Shreyasi and Singh, Shampa and Dubey, Alok Kumar and Mallik, Roop} } @article {714, title = {Distinct spatial and molecular features of notch pathway assembly in regulatory T cells.}, journal = {Sci Signal}, volume = {5}, year = {2012}, month = {2012 Jul 24}, pages = {ra53}, abstract = {

Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor-dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (T(regs)) in vitro and in vivo and was compromised by T cell-specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1(-/-) T(regs) from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin complex 2 (mTORC2) for this cell survival function. Biochemical and imaging approaches revealed a membrane-proximal complex containing NICD and the mTORC2 component Rictor, and this complex was stabilized by specific interactions with the Notch ligand Delta-like-1 and mediated the survival of T(regs). Together, our evidence for the spatial control of Notch and the crosstalk of Notch signaling with other pathways reveals coupling between the localization of Notch and diverse intracellular signaling pathways.

}, keywords = {Animals, Apoptosis, Blotting, Western, Carrier Proteins, Cell Line, Cell Membrane, Cell Survival, Flow Cytometry, Gene Knockout Techniques, Humans, Immunoprecipitation, Intercellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Phosphatidylinositol 3-Kinase, Rapamycin-Insensitive Companion of mTOR Protein, Receptor Cross-Talk, Receptor, Notch1, Signal Transduction, T-Lymphocytes, Regulatory, Trans-Activators, Transcription Factors}, issn = {1937-9145}, doi = {10.1126/scisignal.2002859}, author = {Perumalsamy, Lakshmi R and Marcel, Nimi and Kulkarni, Sneha and Radtke, Freddy and Sarin, Apurva} } @article {480, title = {Drosophila protein interaction map (DPiM): a paradigm for metazoan protein complex interactions. [Drosophila facility]}, journal = {Fly (Austin)}, volume = {6}, year = {2012}, month = {2012 Oct-Dec}, pages = {246-53}, abstract = {

Proteins perform essential cellular functions as part of protein complexes, often in conjunction with RNA, DNA, metabolites and other small molecules. The genome encodes thousands of proteins but not all of them are expressed in every cell type; and expressed proteins are not active at all times. Such diversity of protein expression and function accounts for the level of biological intricacy seen in nature. Defining protein-protein interactions in protein complexes, and establishing the when, what and where of potential interactions, is therefore crucial to understanding the cellular function of any protein-especially those that have not been well studied by traditional molecular genetic approaches. We generated a large-scale resource of affinity-tagged expression-ready clones and used co-affinity purification combined with tandem mass-spectrometry to identify protein partners of nearly 5,000 Drosophila melanogaster proteins. The resulting protein complex "map" provided a blueprint of metazoan protein complex organization. Here we describe how the map has provided valuable insights into protein function in addition to generating hundreds of testable hypotheses. We also discuss recent technological advancements that will be critical in addressing the next generation of questions arising from the map.

}, keywords = {Animals, Cell Line, Computational Biology, Drosophila melanogaster, Drosophila Proteins, Models, Biological, Protein Interaction Mapping, Protein Interaction Maps}, issn = {1933-6942}, doi = {10.4161/fly.22108}, author = {Guruharsha, K G and Obar, Robert A and Mintseris, Julian and Aishwarya, K and Krishnan, R T and VijayRaghavan, K and Artavanis-Tsakonas, Spyros} }