Bio21 - Research Publications

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    FcRn mediates fast recycling of endocytosed albumin and IgG from early macropinosomes in primary macrophages
    Toh, WH ; Louber, J ; Mahmoud, IS ; Chia, J ; Bass, GT ; Dower, SK ; Verhagen, AM ; Gleeson, PA ; Lennon-Duménil, A-M (COMPANY BIOLOGISTS LTD, 2020-03)
    The neonatal Fc receptor (FcRn) rescues albumin and IgG from degradation following endocytosis and thereby extends the half-life of these plasma proteins. However, the pathways for the uptake of these soluble FcRn ligands, and the recycling itinerary of the FcRn-ligand complexes, have not been identified in primary cells. Here, we have defined the recycling of human albumin and IgG in primary mouse macrophages selectively expressing the human FcRn. Albumin is internalised by macropinocytosis; in the absence of FcRn, internalised albumin is rapidly degraded, while in the presence of FcRn albumin colocalises to SNX5-positive membrane domains and is partitioned into tubules emanating from early macropinosomes for delivery in transport carriers to the plasma membrane. Soluble monomeric IgG was also internalised by macropinocytosis and rapidly recycled by the same pathway. In contrast, the fate of IgG bound to surface Fcγ receptors differed from monomeric IgG endocytosed by macropinocytosis. Overall, our findings identify a rapid recycling pathway for FcRn ligands from early macropinosomes to the cell surface of primary cells.
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    A TOOLKIT FOR THE QUANTITATIVE ANALYSIS OF THE SPATIAL DISTRIBUTION OF CELLS OF THE TUMOR IMMUNE MICROENVIRONMENT
    Trigos, A ; Yang, T ; Feng, Y ; Ozcoban, V ; Doyle, M ; Pasam, A ; Kocovski, N ; Pizzolla, A ; Huang, Y-K ; Bass, G ; Keam, S ; Speed, T ; Neeson, P ; Sandhu, S ; Goode, D (BMJ PUBLISHING GROUP, 2020-11)
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    Half-life-extended recombinant coagulation factor IX-albumin fusion protein is recycled via the FcRn-mediated pathway
    Chia, J ; Louber, J ; Glauser, I ; Taylor, S ; Bass, GT ; Dower, SK ; Gleeson, PA ; Verhagen, AM (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2018-04-27)
    The neonatal Fc receptor (FcRn) has a pivotal role in albumin and IgG homeostasis. Internalized IgG captured by FcRn under acidic endosomal conditions is recycled to the cell surface where exocytosis and a shift to neutral pH promote extracellular IgG release. Although a similar mechanism is proposed for FcRn-mediated albumin intracellular trafficking and recycling, this pathway is less well defined but is relevant to the development of therapeutics exploiting FcRn to extend the half-life of short-lived plasma proteins. Recently, a long-acting recombinant coagulation factor IX-albumin fusion protein (rIX-FP) has been approved for the management of hemophilia B. Fusion to albumin potentially enables internalized proteins to engage FcRn and escape lysosomal degradation. In this study, we present for the first time a detailed investigation of the FcRn-mediated recycling of albumin and the albumin fusion protein rIX-FP. We demonstrate that following internalization via FcRn at low pH, rIX-FP, like albumin, is detectable within the early endosome and rapidly (within 10-15 min) traffics into the Rab11+ recycling endosomes, from where it is exported from the cell. Similarly, rIX-FP and albumin taken up by fluid-phase endocytosis at physiological pH traffics into the Rab11+ recycling compartment in FcRn-positive cells but into the lysosomal compartment in FcRn-negative cells. As expected, recombinant factor IX (without albumin fusion) and an FcRn interaction-defective albumin variant localized to the lysosomal compartments of both FcRn-expressing and nonexpressing cells. These results indicate that FcRn-mediated recycling via the albumin moiety is a mechanism for the half-life extension of rIX-FP observed in clinical studies.