Biology subjects

Futerman, A. H.

Publications and source records attributed to Futerman, A. H..

3 recordsLinked to original sources

bioRxiv2025

Ceramide Connects TNF-α Signaling to Organelle Biophysical Remodeling

Ceramides are essential bioactive lipids involved in cell physiology and stress responses, yet the mechanisms linking their biophysical effects on membranes to downstream cellular outcomes remain incompletely understood. Here, we demonstrate that endogenous ceramide generation in response to TNF--induced stress results in the rapid remodeling of the plasma membrane, triggering a cascade of cellular events. Ceramide accumulation increases membrane order and drives the formation of internalizing vesicles enriched in ceramides, which traffic through the endolysosomal system. These vesicles act as carriers that transmit membrane remodeling signals to intracellular compartments, altering their biophysical properties and function. In parallel, ceramide production reprograms lipid droplet metabolism, decreasing polarity and modifying gene expression related to lipid storage. Our findings provide direct evidence that ceramides function as biophysical integrators of the TNF- stress response, coupling membrane order, vesicle trafficking, and lipid metabolic adaptation. This work reveals how localized lipid remodeling at the plasma membrane propagates intracellularly to support cellular adaptation and homeostasis under inflammatory stress.

biophysics↗

bioRxiv2021

FAM57B is a modulator of ceramide synthesis that regulates sphingolipid homeostasis and synaptic composition in the developing brain

The complex 16p11.2 Deletion Syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder and intellectual disability. We demonstrate that 16pdel iPSC differentiated neurons showed augmented local field potential activity and altered ceramide-related lipid species relative to unaffected. FAM57B, a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. In FAM57B mutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency of FAM57B contributes to changes in neuronal activity and function in 16pdel Syndrome, through a crucial role for the gene in lipid metabolism.

neuroscience↗

bioRxiv2021

Cholesteryl Hemiazelate Induces Lysosome Dysfunction and Exocytosis in Macrophages

OBJECTIVEA key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. This event culminates with the loss of cell homeostasis, inflammation and cell death. In this study we propose to identify the chemical etiological factors and understanding the molecular and cellular mechanisms responsible for the impairment of lysosome function in macrophages. APPROACH AND RESULTSUsing shotgun lipidomics we have discovered that a family of oxidized lipids (cholesteryl hemiesters, ChE), end products of oxidation of polyunsaturated cholesteryl esters, occurs at higher concentrations in the plasma of two cohorts of cardiovascular disease patients than in the plasma of a control cohort. Macrophages exposed to the most prevalent ChE, cholesteryl hemiazelate (ChA) exhibit lysosome enlargement, peripheral lysosomal positioning, lysosome dysfunction and lipidosis which are irreversible. The transcriptomic profile of macrophages exposed to ChA indicates that the lysosome pathway is deeply affected and is well correlated with lysosome phenotypic and functional changes. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences to the pathology. CONCLUSIONWe identify ChA not only as one of the molecules involved in the etiology of irreversible lysosome dysfunction culminating with lipidosis but also as a promoter of exocytosis of the dysfunctional lysosomes. The latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.

cell biology↗