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Articles by S. Grinstein
Total Records ( 5 ) for S. Grinstein
  S. Grinstein

Together with the development of genetically encoded fluorescent probes, digital imaging has provided great impetus to the study of cell signaling by providing enhanced sensitivity and much-improved spatial and temporal resolution. We have used phagocytosis as a paradigm of signal transduction, taking advantage of the generous size of phagosomes and of their comparatively leisurely rate of formation. Aided by the design of specific probes, we demonstrated a highly localized and elegantly choreographed sequence of changes in the level of several phosphoinositides and were able to also monitor the fate of phosphatidylserine. The net changes in the content of these anionic phospholipids are accompanied by marked alterations in the surface charge of the membrane of nascent phagosomes. These, in turn, cause the relocation of proteins that associate with the membrane by electrostatic interactions. Our studies suggest that anionic lipids control protein targeting not only through stereospecific recognition by specialized domains but also by electrostatic association mediated by polycationic motifs. The "electrostatic switch" can be turned on or off by altering the charge of the protein ligand (e.g., by phosphorylation) or, alternatively, by modifying the lipid composition of the target membrane.

  T Yeung , B Heit , J. F Dubuisson , G. D Fairn , B Chiu , R Inman , A Kapus , M Swanson and S. Grinstein

During phagocytosis, the phosphoinositide content of the activated membrane decreases sharply, as does the associated surface charge, which attracts polycationic proteins. The cytosolic leaflet of the plasma membrane is enriched in phosphatidylserine (PS); however, a lack of suitable probes has precluded investigation of the fate of this phospholipid during phagocytosis. We used a recently developed fluorescent biosensor to monitor the distribution and dynamics of PS during phagosome formation and maturation. Unlike the polyphosphoinositides, PS persists on phagosomes after sealing even when other plasmalemmal components have been depleted. High PS levels are maintained through fusion with endosomes and lysosomes and suffice to attract cationic proteins like c-Src to maturing phagosomes. Phagocytic vacuoles containing the pathogens Legionella pneumophila and Chlamydia trachomatis, which divert maturation away from the endolysosomal pathway, are devoid of PS, have little surface charge, and fail to recruit c-Src. These findings highlight a function for PS in phagosome maturation and microbial killing.

  G. D Fairn , K Ogata , R. J Botelho , P. D Stahl , R. A Anderson , P De Camilli , T Meyer , S Wodak and S. Grinstein

PIP5K is held at the membrane of forming phagosomes by a conserved, positively charged patch. During particle engulfment, the surface charge of the phagosome decreases, releasing PIP5K and enabling phagocytosis to proceed.

  M Koivusalo , C Welch , H Hayashi , C. C Scott , M Kim , T Alexander , N Touret , K. M Hahn and S. Grinstein

Inhibitors of Na+/H+ exchange proteins block macropinocytosis by lowering the pH near the plasma membrane, which in turn inhibits actin remodeling by Rho family GTPases.

  M Bohdanowicz , G Cosio , J. M Backer and S. Grinstein

Actin polymerization drives the extension of pseudopods that trap and engulf phagocytic targets. The polymerized actin subsequently dissociates as the phagocytic vacuole seals and detaches from the plasma membrane. We found that phagosomes formed by engagement of integrins that serve as complement receptors (CR3) undergo secondary waves of actin polymerization, leading to the formation of "comet tails" that propel the vacuoles inside the cells. Actin tail formation was accompanied by and required de novo formation of PI(3,4)P2 and PI(3,4,5)P3 on the phagosomal membrane by class I phosphoinositide 3-kinases (PI3Ks). Although the phosphatidylinositide phosphatase Inpp5B was recruited to nascent phagosomes, it rapidly detached from the membrane after phagosomes sealed. Detachment of Inpp5B required the formation of PI(3)P. Thus, class III PI3K activity was also required for the accumulation of PI(4,5)P2 and PI(3,4,5)P3 and for actin tail formation. These experiments reveal a new PI(3)P-sensitive pathway leading to PI(3,4)P2 and PI(3,4,5)P3 formation and signaling in endomembranes.

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