Molecular mechanisms of water homeostasis: Cellular communication, immunity and infection
Lead Research Organisation:
Imperial College London
Department Name: Infectious Disease
Abstract
Water is the major constituent of cells and must by tightly regulated because its availability affects all biochemical processes. Dynamic cohesive networks of water molecules are disrupted by solutes because water around them can't move freely, forming more structured 'hydration layers' with less potential energy to do work than 'free' water molecules further from the solute. Aqueous solutions therefore reorganise to maximise the potential energy of water. This depends on the solute's concentration and nature: small, charged molecules have less impact on water compared to proteins with large surface areas that may interact unfavourably with water.
My team recently found that water behaves very differently in the crowded cellular environment compared to dilute solutions: It becomes very sensitive to small changes in temperature and protein concentration. As temperature falls over the physiological range, more and more water molecules are held in protein hydration layers. This reduces the 'free' water available in cells. Strikingly, we found cells survive extreme cold conditions (0C for 24h) when their growth medium is diluted: Water enters cells by osmosis which restores water balance. Combining two stresses with opposite effects on 'free' water availability prevents cell death and illustrates how critical water's "goldilocks" zone is to life.
My team also found new regulatory mechanisms of cellular water balance operating over very short (secs) and longer (hrs) timeframes without any damaging changes in volume. This allows cells to continue functioning efficiently despite natural fluctuations in protein levels, temperature or external salt levels. We also found sequestration of proteins into fluid accumulations called biomolecular condensates (BMCs) releases water molecules from hydration layers, whereas water is recruited to hydration layers when proteins leave BMCs: a rapid feedback mechanisms that adjusts 'free' water availability in cells. This suggests cells may use water to quickly relay signals by altering protein location and activity.
Protein levels change over daily cycles and in response to growth signals. Over such timescales, my team found ions move out of cells as protein levels increase and vice versa, facilitated by specific ion transporters. By extension, when membrane channel opening promotes ion efflux in cells, excess 'free' water should leave and cause cells to shrink but they do not. I predict this ion exodus instead drives proteins out of BMCs and other cell compartments to 'soak up' excess water in their hydration layers and this alters protein activity.
From these insights, we will answer three questions:
1. Does water acts as a cellular messenger?
We will identify water-responsive sensors and how they signal e.g. timing cues to cellular body clocks, immune cell activation, brain cell (astrocyte) activity during learning.
2. Does water regulate inflammation and antiviral defences?
Cellular water responds to temperature. We will test how fever directly affects inflammation, which is initiated in response to diverse danger signals but requires ion efflux. I theorise release of BMC components activate vital immune processes.
3. Do viruses exploit water balance to promote replication and transmission?
Viruses must minimise disruption to water balance to synthesise their proteins and produce virus before cells die. We will ask how cellular water impacts infection and how viruses manipulate ion transport and BMCs.
By answering these questions we will better understand how cells communicate, their immune responses, infection susceptibility and new virus production for disease transmission. My research will inform future interventions to prevent overactivation of inflammation and virus spread. Working out fundamental mechanisms of host cell biology will also provide insight into cell growth and movement, brain signalling, aging and neurodegeneration, and processes like hibernation.
My team recently found that water behaves very differently in the crowded cellular environment compared to dilute solutions: It becomes very sensitive to small changes in temperature and protein concentration. As temperature falls over the physiological range, more and more water molecules are held in protein hydration layers. This reduces the 'free' water available in cells. Strikingly, we found cells survive extreme cold conditions (0C for 24h) when their growth medium is diluted: Water enters cells by osmosis which restores water balance. Combining two stresses with opposite effects on 'free' water availability prevents cell death and illustrates how critical water's "goldilocks" zone is to life.
My team also found new regulatory mechanisms of cellular water balance operating over very short (secs) and longer (hrs) timeframes without any damaging changes in volume. This allows cells to continue functioning efficiently despite natural fluctuations in protein levels, temperature or external salt levels. We also found sequestration of proteins into fluid accumulations called biomolecular condensates (BMCs) releases water molecules from hydration layers, whereas water is recruited to hydration layers when proteins leave BMCs: a rapid feedback mechanisms that adjusts 'free' water availability in cells. This suggests cells may use water to quickly relay signals by altering protein location and activity.
Protein levels change over daily cycles and in response to growth signals. Over such timescales, my team found ions move out of cells as protein levels increase and vice versa, facilitated by specific ion transporters. By extension, when membrane channel opening promotes ion efflux in cells, excess 'free' water should leave and cause cells to shrink but they do not. I predict this ion exodus instead drives proteins out of BMCs and other cell compartments to 'soak up' excess water in their hydration layers and this alters protein activity.
From these insights, we will answer three questions:
1. Does water acts as a cellular messenger?
We will identify water-responsive sensors and how they signal e.g. timing cues to cellular body clocks, immune cell activation, brain cell (astrocyte) activity during learning.
2. Does water regulate inflammation and antiviral defences?
Cellular water responds to temperature. We will test how fever directly affects inflammation, which is initiated in response to diverse danger signals but requires ion efflux. I theorise release of BMC components activate vital immune processes.
3. Do viruses exploit water balance to promote replication and transmission?
Viruses must minimise disruption to water balance to synthesise their proteins and produce virus before cells die. We will ask how cellular water impacts infection and how viruses manipulate ion transport and BMCs.
By answering these questions we will better understand how cells communicate, their immune responses, infection susceptibility and new virus production for disease transmission. My research will inform future interventions to prevent overactivation of inflammation and virus spread. Working out fundamental mechanisms of host cell biology will also provide insight into cell growth and movement, brain signalling, aging and neurodegeneration, and processes like hibernation.
People |
ORCID iD |
| Rachel Edgar (Principal Investigator / Fellow) |