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Massol, Ramiro

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Massol

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Ramiro

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Massol, Ramiro

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2009 - 200912010 - 20132

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Author's Publications: search.filters.isAuthorOfPublication.f6f2e761-99af-443b-85e8-27c78efebab2

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    Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds
    (The Rockefeller University Press, 2013) Martinelli, Roberta; Kamei, Masataka; Sage, Peter; Massol, Ramiro; Varghese, Laya; Sciuto, Tracey; Toporsian, Mourad; Dvorak, Ann; Kirchhausen, Tomas; Springer, Timothy; Carman, Christopher
    Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these “micro-wounds” to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species–dependent self-restorative actin remodeling dynamics.
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    Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins
    (Frontiers Media S.A., 2012) Cho, JinAh; Chinnapen, Daniel; Aamar, Emil; te Welscher, Yvonne Maria; Lencer, Wayne; Massol, Ramiro
    Some bacterial toxins and viruses have evolved the capacity to bind mammalian glycosphingolipids to gain access to the cell interior, where they can co-opt the endogenous mechanisms of cellular trafficking and protein translocation machinery to cause toxicity. Cholera toxin (CT) is one of the best-studied examples, and is the virulence factor responsible for massive secretory diarrhea seen in cholera. CT enters host cells by binding to monosialotetrahexosylganglioside (GM1 gangliosides) at the plasma membrane where it is transported retrograde through the trans-Golgi network (TGN) into the endoplasmic reticulum (ER). In the ER, a portion of CT, the CT-A1 polypeptide, is unfolded and then “retro-translocated” to the cytosol by hijacking components of the ER associated degradation pathway (ERAD) for misfolded proteins. CT-A1 rapidly refolds in the cytosol, thus avoiding degradation by the proteasome and inducing toxicity. Here, we highlight recent advances in our understanding of how the bacterial AB5 toxins induce disease. We highlight the molecular mechanisms by which these toxins use glycosphingolipid to traffic within cells, with special attention to how the cell senses and sorts the lipid receptors. We also discuss several new studies that address the mechanisms of toxin unfolding in the ER and the mechanisms of CT A1-chain retro-translocation to the cytosol.
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    The Recycling and Transcytotic Pathways for IgG Transport by FcRn are Distinct and Display an Inherent Polarity
    (Rockefeller University Press, 2009) Tzaban, Salit; Massol, Ramiro; Yen, Elizabeth Hechavarria; Hamman, Wendy; Frank, Scott; Lapierre, Lynne A.; Hansen, Steen; Goldenring, James R.; Blumberg, Richard; Lencer, Wayne
    The Fc receptor FcRn traffics immunoglobulin G (IgG) in both directions across polarized epithelial cells that line mucosal surfaces, contributing to host defense. We show that FcRn traffics IgG from either apical or basolateral membranes into the recycling endosome (RE), after which the actin motor myosin Vb and the GTPase Rab25 regulate a sorting step that specifies transcytosis without affecting recycling. Another regulatory component of the RE, Rab11a, is dispensable for transcytosis, but regulates recycling to the basolateral membrane only. None of these proteins affect FcRn trafficking away from lysosomes. Thus, FcRn transcytotic and recycling sorting steps are distinct. These results are consistent with a single structurally and functionally heterogeneous RE compartment that traffics FcRn to both cell surfaces while discriminating between recycling and transcytosis pathways polarized in their direction of transport.