Medical Biology - Research Publications

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Author: Alexander, Warren × Author: Hilton, Douglas × End date: 2021 × Start date: 2020 ×

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    Membrane budding is a major mechanism of in vivo platelet biogenesis
    Potts, KS ; Farley, A ; Dawson, CA ; Rimes, J ; Biben, C ; de Graaf, C ; Potts, MA ; Stonehouse, OJ ; Carmagnac, A ; Gangatirkar, P ; Josefsson, EC ; Anttila, C ; Amann-Zalcenstein, D ; Naik, S ; Alexander, WS ; Hilton, DJ ; Hawkins, ED ; Taoudi, S (ROCKEFELLER UNIV PRESS, 2020-09)
    How platelets are produced by megakaryocytes in vivo remains controversial despite more than a century of investigation. Megakaryocytes readily produce proplatelet structures in vitro; however, visualization of platelet release from proplatelets in vivo has remained elusive. We show that within the native prenatal and adult environments, the frequency and rate of proplatelet formation is incompatible with the physiological demands of platelet replacement. We resolve this inconsistency by performing in-depth analysis of plasma membrane budding, a cellular process that has previously been dismissed as a source of platelet production. Our studies demonstrate that membrane budding results in the sustained release of platelets directly into the peripheral circulation during both fetal and adult life without induction of cell death or proplatelet formation. In support of this model, we demonstrate that in mice deficient for NF-E2 (the thrombopoietic master regulator), the absence of membrane budding correlates with failure of in vivo platelet production. Accordingly, we propose that membrane budding, rather than proplatelet formation, supplies the majority of the platelet biomass.
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    Proteomic analyses reveal that immune integrins are major targets for regulation by Membrane-Associated Ring-CH (MARCH) proteins MARCH2, 3, 4 and 9
    Sandow, JJ ; Webb, AI ; Stockwell, D ; Kershaw, NJ ; Tan, C ; Ishido, S ; Alexander, WS ; Hilton, DJ ; Babon, JJ ; Nicola, NA (WILEY, 2021-06)
    MARCH proteins are membrane-associated Ring-CH E3 ubiquitin ligases that dampen immune responses by downregulating cell surface expression of major histocompatibility complexes I and II as well as immune co-stimulatory receptors. We recently showed that MARCH2,3,4 and 9 also downregulate cell surface expression of the inflammatory cytokine receptor for interleukin-6 (IL6Rα). Here we use over-expression of these MARCH proteins in the M1 myeloid leukaemia cell line and cell surface proteomic analyses to globally analyse other potential targets of these proteins. A large range of cell surface proteins regulated by more than one MARCH protein in addition to several MARCH protein-specific cell surface targets were identified most of which were downregulated by MARCH expression. Prominent among these were several integrin complexes associated with immune cell homing, adhesion and migration. Integrin α4β1 (VLA4 or VCAM-1 receptor) was downregulated only by MARCH2 and we showed that in MARCH2 knockout mice, Integrin α4 was upregulated specifically in mature B-lymphocytes and this was accompanied by decreased numbers of B-cells in the spleen.