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      ATP11c is critical for phosphatidylserine internalization and B lymphocyte differentiation

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          Abstract

          Subcompartments of the plasma membrane are believed to be critical for lymphocyte responses but few genetic tools exist to test their function. Here we describe a new X-linked B cell deficiency syndrome in mice caused by mutations in Atp11c, a member of the P4 ATPase family thought to serve as flippases concentrating aminophospholipids in the cytoplasmic leaflet of cell membranes. Defective ATP11c decreased the rate of phosphatidylserine translocation in pro-B cells, greatly reduced pre-B and B cell numbers independent of Bcl2-inhibited apoptosis or immunoglobulin gene rearrangement and abolished pre-B cell expansion in response to an Il7 transgene. The only other abnormalities noted were anemia, hyperbilirubinemia and hepatocellular carcinoma. These results identify an intimate connection between phospholipid transport and B lymphocyte function.

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          Most cited references36

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          The distribution and function of phosphatidylserine in cellular membranes.

          Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in eukaryotic membranes. PS directs the binding of proteins that bear C2 or gamma-carboxyglutamic domains and contributes to the electrostatic association of polycationic ligands with cellular membranes. Rather than being evenly distributed, PS is found preferentially in the inner leaflet of the plasma membrane and in endocytic membranes. The loss of PS asymmetry is an early indicator of apoptosis and serves as a signal to initiate blood clotting. This review discusses the determinants and functional implications of the subcellular distribution and membrane topology of PS.
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            Membrane phosphatidylserine regulates surface charge and protein localization.

            Electrostatic interactions with negatively charged membranes contribute to the subcellular targeting of proteins with polybasic clusters or cationic domains. Although the anionic phospholipid phosphatidylserine is comparatively abundant, its contribution to the surface charge of individual cellular membranes is unknown, partly because of the lack of reagents to analyze its distribution in intact cells. We developed a biosensor to study the subcellular distribution of phosphatidylserine and found that it binds the cytosolic leaflets of the plasma membrane, as well as endosomes and lysosomes. The negative charge associated with the presence of phosphatidylserine directed proteins with moderately positive charge to the endocytic pathway. More strongly cationic proteins, normally associated with the plasma membrane, relocalized to endocytic compartments when the plasma membrane surface charge decreased on calcium influx.
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              Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival.

              Survival of naive T cells is dependent upon IL-7, which is present in vivo in limiting amounts with the result that naive T cells must compete for IL-7-mediated survival signals. It would seem imperative during T cell homeostasis that limiting IL-7 be shared by the greatest possible number of T cells. We now describe a novel regulatory mechanism that specifically suppresses IL7Ralpha transcription in response to IL-7 and other prosurvival cytokines (IL-2, IL-4, IL-6, and IL-15). Consequently, IL7R expression is reduced on T cells that have received cytokine-mediated survival signals so they do not compete with unsignaled T cells for remaining IL-7. Interestingly, cytokine-mediated suppression of IL7Ralpha transcription involves different molecular mechanisms in CD4+ and CD8+ T cells, as CD8+ T cells utilize the transcriptional repressor GFI1 while CD4+ T cells do not. We suggest that this homeostatic regulatory mechanism promotes survival of the maximum possible number of T cells for the amount of IL-7 available.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature Immunology
                1529-2908
                1529-2916
                7 September 2011
                20 March 2011
                May 2011
                6 February 2012
                : 12
                : 5
                : 441-449
                Affiliations
                [1 ]Ramaciotti Immunization Genomics Laboratory, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra ACT 0200, Australia
                [2 ]Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra ACT 0200, Australia
                [3 ]Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia
                [4 ]Gastroenterology and Hepatology Unit, Australian National University Medical School, The Canberra Hospital, Canberra, ACT 2605, Australia
                [5 ]Immunology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia, and WCU-IBB Program, Postech, Pohang, Korea
                [6 ]Division of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia
                Author notes
                [#]

                These authors contributed equally.

                Article
                nihpa275148
                10.1038/ni.2011
                3272780
                21423173
                2fb0375e-1d63-4bee-bae1-c9bb87059b57

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                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: U54 AI054523-01 || AI
                Categories
                Article

                Immunology
                Immunology

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