Biology subjects

Saric, A.

Publications and source records attributed to Saric, A..

39 records · Page 3Linked to original sources

bioRxiv2019

Transitions in filament geometry drive ESCRT-III-mediated membrane remodelling and fission

ESCRT-III is an evolutionarily conserved membrane remodeling machinery that, with the Vps4 ATPase, forms filaments able to cut biological membranes from the cytosolic side. This activity of ESCRT-III is essential for the final stage of cell division in archaea and in many eukaryotes, the formation of vesicles, the creation of exosomes, the release of viruses such as HIV-1 and Ebola, and for the repair and sealing of cellular membranes. While there has been recent rapid progress in describing the biochemical and cell biology details of different ESCRT-III functions, we lack an understanding of the physical mechanism involved in ESCRT-III-mediated membrane remodelling. Here, through the development of coarse-grained molecular dynamic simulations, we present a minimal model that captures the ability of ESCRT-III to induce experimentally reported cases of ESCRT-III driven membrane sculpting, including the formation of cones and tubules, and membrane scission. This model suggests a universal physical mechanism of action, that differs from that of other cytoskeletal elements, whereby a change in the twist of membrane bound ESCRT-III filaments drives transitions between a flat spiral and a 3D helix to induce membrane deformation and scission. We expect the mechanistic principles revealed here to be useful in manipulating ESCRT-III-driven processes in cells and in guiding the engineering of synthetic membrane-sculpting systems.

biophysics↗

bioRxiv2019

Dynamic clustering regulates activity of mechanosensitive membrane channels

Mechanosensitive channels regulate the flux of solutes between the cell and its environment in response to mechanical stimuli. Recent in vitro experiments have suggested that bacterial mechanosensitive channels separate into 2D liquid-like clusters, exhibiting cooperative activity. To understand the functional role of the process and its physical mechanism, we develop a coarse-grained model of mechanosensitive channels embedded in a membrane, exposed to an osmotic shock. We find that the channel aggregation into liquid-like clusters promotes the closure of individual channels. The extent of clustering is highly dependent on the channel concentration and membrane stress. We show that this behaviour yields a tightly regulated gating system, whereby at high tensions channels gate individually, and at lower tensions the channels spontaneously aggregate and inactivate. We suggest that this positive feedback protects the cell against excessive loss of cytoplasmic content. Our results point to a novel role of functional micro-phase separation in the cell membrane.

biophysics↗

bioRxiv2018

Lysosome expansion by selective translation of lysosomal transcripts during phagocyte activation

The mechanisms that govern organelle adaptation and remodeling remain poorly defined. The endo-lysosomal system degrades cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, endosomes and lysosomes (endo-lysosomes) are kingpin organelles since they are essential to kill pathogens and process and present antigens. During phagocyte activation, endo-lysosomes undergo a morphological transformation, going from a collection of dozens of globular structures to a tubular network in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that the endo-lysosomal system undergoes an expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Endo-lysosomal expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly largely independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation, which appears to be mediated by both, S6Ks and 4E-BPs. Moreover, we show that stimulation of RAW cells with LPS alters translation of a subset but not all of mRNAs encoding endo-lysosomal proteins, thereby suggesting that endo-lysosome expansion is accompanied by functional remodelling. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for endo-lysosome expansion that relies on mTORC1-dependent translation to stimulate endo-lysosome biogenesis in response to an infection signal.

cell biology↗