bims-momema 2022-04-03 papers

Issue of 2022‒04‒03
two papers selected by
Harilaos Filippakis
Harvard University

ACS Infect Dis. 2022 Mar 31.

Evaluation of Phenol-Substituted Diphyllin Derivatives as Selective Antagonists for Ebola Virus Entry.

Caroline B Plescia, Aaron R Lindstrom, Maritza V Quintero, Patrick Keiser, Manu Anantpadma, Robert Davey, Robert V Stahelin, V Jo Davisson.

Ebola virus (EBOV) is an aggressive filoviral pathogen that can induce severe hemorrhagic fever in humans with up to 90% fatality rate. To date, there are no clinically effective small-molecule drugs for postexposure therapies to treat filoviral infections. EBOV cellular entry and infection involve uptake via macropinocytosis, navigation through the endocytic pathway, and pH-dependent escape into the cytoplasm. We report the inhibition of EBOV cell entry via selective inhibition of vacuolar (V)-ATPase by a new series of phenol-substituted derivatives of the natural product scaffold diphyllin. In cells challenged with Ebola virus, the diphyllin derivatives inhibit viral entry dependent upon structural variations to low nanomolar potencies. Mechanistically, the diphyllin derivatives had no effect on uptake and colocalization of viral particles with endocytic marker LAMP1 but directly modulated endosomal pH. The most potent effects were reversible exhibiting higher selectivity than bafilomycin or the parent diphyllin. Unlike general lysosomotrophic agents, the diphyllin derivatives showed no major disruptions of endocytic populations or morphology when examined with Rab5 and LAMP1 markers. The dilated vacuole phenotype induced by apilimod treatment or in constitutively active Rab5 mutant Q79L-expressing cells was both blocked and reversed by the diphyllin derivatives. The results are consistent with the action of the diphyllin scaffold as a selective pH-dependent viral entry block in late endosomes. Overall, the compounds show improved selectivity and minimal cytotoxicity relative to classical endosomal acidification blocking agents.

Keywords: V-ATPase inhibitor; diphyllin; endosome trafficking; macropinocytosis; viral entry inhibitor

DOI: https://doi.org/10.1021/acsinfecdis.1c00474

Mol Biol Cell. 2022 Mar 30. mbcE21120623

Growth cone macropinocytosis of neurotrophin receptor and neuritogenesis are regulated by Neuron Navigator 1.

Regina M Powers, Ray Daza, Alanna E Koehler, Julien Courchet, Barbara Calabrese, Robert F Hevner, Shelley Halpain.

Neuron Navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone, and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin BDNF (brain-derived neurotropic factor). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.

DOI: https://doi.org/10.1091/mbc.E21-12-0623