The role of the cytoskeleton and molecular motors in endosomal dynamics

Granger, Elizabeth; McNee, Gavin; Allan, Viki; Woodman, Philip

doi:10.1016/j.semcdb.2014.04.011

Cited by 229 publications

(228 citation statements)

References 167 publications

(189 reference statements)

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“…Thus, both processes are affected by nanoART and URMC-099. Indeed, the combination of nanoATV and URMC-099 attenuates giant cell formation, most likely by affecting endosomal and vesicular trafficking and reducing cytoskeletal rearrangements (61). These data support the notion that URMC-099 induces the changes in endosomal trafficking that affect known intracellular ARV particle accumulation (11).…”

Section: Discussionsupporting

confidence: 66%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

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Section: Discussionsupporting

confidence: 66%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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“…6). The potential membranous scissions, as suggested by TEM, may be conducive to turnover and sorting of endosomal/lysosomal vesicles for fusion with PVs during cytoskeletal movements (38). The working model for Wnt5a signaling-mediated cytoskeletal dynamics that involves vesicle fusion with PVs, formation of laminated bodies, and PV degradation is depicted in Fig.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Chakraborty

Kurati

Mahata

et al. 2017

The Journal of Immunology

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Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug–sensitive and –resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho–mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani–infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV–endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance.

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“…Kinesin proteins may direct MVBs to plus end microtubule releasing MVBs as exosomes and dyneins family could guide MVBs toward lysosomes. 83 Understanding the signaling and the molecular clues that determine the traffic of cargo toward the lysosomes or the plasma membrane will allow us to manipulate the flux between degradation and secretion and could have immense relevance in the control of different pathological situations such as neurodegenerative or inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Role of exosomes in the protection of cellular homeostasis

Desdín-Micó

Mittelbrunn

2016

Cell Adhesion & Migration

143

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Due to their ability to shuttle proteins, lipids and genetic material between distant cells, exosomes promote extensive phenotypic changes in recipient cells, modulating immune responses, cellular migration, cancer metastasis or the spreading of neurotoxic protein aggregates in neurodegenerative diseases. Besides intercellular communication, exosome biogenesis and secretion permit the rapid release of a selective repertoire of compounds, conferring cells with an additional mechanism to fight alterations in protein, lipid or RNA homeostasis during stress or pathological conditions. Here, we review the dual role of the different quality control mechanisms arising from the endolysosomal system and the diverse situations that control the decision between degradation or secretion. The crosstalk between exosome secretion and the different cellular degradation mechanisms confers an additional layer of protection to maintain cellular integrity and homeostasis in a number of physiological and pathological conditions.

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The role of the cytoskeleton and molecular motors in endosomal dynamics

Abstract: HighlightsTransport between endocytic organelles involves microtubule and actin based molecular motors.Both cytoskeletal systems contribute to membrane deformation and scission.Transport of endosomes to and from the cell cortex requires transfer between actin and microtubules.

Cited by 229 publications

References 167 publications

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Role of exosomes in the protection of cellular homeostasis

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