Biology subjects

Lucas, R. M.

Publications and source records attributed to Lucas, R. M..

4 recordsLinked to original sources

bioRxiv2024

Macrophage migration-dependent retraction fibers and migrasomes - a structural basis for spatiotemporal cytokine secretion.

Migrating cells leave behind trails of matrix-bound retraction fibers and migrasomes, but their cell-specific physiological functions are largely unknown. We comprehensively characterize retraction fibers and migrasomes of migrating macrophages in mouse and zebrafish in vitro and in vivo models. These structures share common and macrophage-centric components of tetraspanin enriched microdomains (TEMs) including tetraspanin 4 (TSPAN4), the integrin CD11b and the pTRAP, SCIMP; like TSPAN4, we show that SCIMP expression modulates retraction fiber and migrasome formation. In immune-activated migrating macrophages, rear-positioned recycling endosomes regulate the secretory trafficking of newly synthesized inflammatory cytokines into retraction fibers and migrasomes. Transmembrane TNF is delivered via SNARE-mediated carriers to the cell surface and to the surfaces of both retraction fibers and migrasomes, from where it can be released. Retraction fibers are thus newly identified here as cytokine secretion sites, and along with migrasomes they allow migrating macrophages to secrete more cytokine compared to stationary cells. Whereas cytokine secretion has been viewed as a process of ad hoc diffusion, instead, we reveal a new mechanism of migration-dependent, localized deposition and spatiotemporal release of bioactive cytokines from RFs and migrasomes. Cytokine deployment is thus organized in a constrained manner facilitating direct influence on local inflammatory responses.

cell biology↗

bioRxiv2021

Metabolic dysfunction induced by high-fat diet modulates hematopoietic stem and myeloid progenitor cells in brown adipose tissue of mice

Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC) - which give rise to DCs - in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the whitening effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.

cell biology↗

bioRxiv2019

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation.

Mutations in LRRK2 are the most common cause of dominantly inherited Parkinsons disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of -synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein homeostasis, however how PD mutations in LRRK2 may lead to accumulation of ubiquitinated protein aggregates remains unclear. A main cellular pathway to remove aggregated ubiquitinated proteins is aggrephagy: the histone deacetylase HDAC6 recognizes ubiquitinated misfolded proteins and recruits them to the molecular motor cytoplasmic dynein which transports them to the perinuclear region where they are trapped in aggresomes that are subsequently removed by macroautophagy. Here we identified HDAC6 as a novel LRRK2 substrate and show that LRRK2 regulates HDAC6-dependent aggresome formation. LRRK2 directly interacted with the HDAC6 deacetylase domains via its Roc domain and phosphorylated HDAC6 on serine-22. Serine-22 phosphorylation of HDAC6 enhanced its interaction with cytoplasmic dynein and stimulated recruitment of ubiquitinated proteins to aggresomes. Knockdown or knockout of LRRK2 impaired HDAC6-mediated aggresome formation. PD mutant LRRK2 G2019S showed reduced interaction with HDAC6 and did not support aggresome formation to the same extend as wild type LRRK2. This was recapitulated in LRRK2 G2019S patient-derived iAstrocytes that showed an aggresome formation defect. In conclusion our data reveal HDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.

neuroscience↗

bioRxiv2017

REMAP: An online remote sensing application for land cover classification and monitoring

O_LIRecent assessments of progress towards global conservation targets have revealed a paucity of indicators suitable for assessing the changing state of ecosystems. Moreover, land managers and planners are often unable to gain timely access to maps they need to support their routine decision-making. This deficiency is partly due to a lack of suitable data on ecosystem change, driven mostly by the considerable technical expertise needed to make ecosystem maps from remote sensing data.\nC_LIO_LIWe have developed a free and open-access online remote sensing and environmental modelling application, REMAP (the remote ecosystem monitoring and assessment pipeline; https://remap-app.org) that enables volunteers, managers, and scientists with little or no experience in remote sensing to develop high-resolution classified maps of land cover and land use change over time.\nC_LIO_LIREMAP utilizes the geospatial data storage and analysis capacity of the Google Earth Engine, and requires only spatially resolved training data that define map classes of interest (e.g., ecosystem types). The training data, which can be uploaded or annotated interactively within REMAP, are used in a random forest classification of up to 13 publicly available predictor datasets to assign all pixels in a focal region to map classes. Predictor datasets available in REMAP represent topographic (e.g. slope, elevation), spectral (Landsat Archive image composites) and climatic variables (precipitation, temperature) that can inform on the distribution of ecosystems and land cover classes.\nC_LIO_LIThe ability of REMAP to develop and export high-quality classified maps in a very short (<10 minute) time frame represents a considerable advance towards globally accessible and free application of remote sensing technology. By enabling access to data and simplifying remote sensing classifications, REMAP can catalyse the monitoring of land use and change to support environmental conservation, including developing inventories of biodiversity, identifying hotspots of ecosystem diversity, ecosystem-based spatial conservation planning, mapping ecosystem loss at local scales, and supporting environmental education initiatives.\nC_LI

ecology↗