Rescue machinery prevents cellular suicide

Cells use the ESCRT-III machinery to repair the cell envelope by releasing bubbl

Cells use the ESCRT-III machinery to repair the cell envelope by releasing bubbles of broken membrane. Plasma membrane is stained in blue, the ESCRT-III machinery in red. Kateryna Shkarina, DB

In a new study published in Science a team led by Prof. Petr Broz from the Department of Biochemistry identify a new mechanism to control immune cell death associated with inflammatory diseases, including sepsis, inflammatory bowel disease (IBD), and arthritis.

Programmed cell death is an important mechanism by which our body removes old, non-functional or unwanted cells. A particular form of cell suicide - known as pyroptosis - is used to kill cells that are infected with pathogenic bacteria or viruses. The ‘executioner’ of pyroptosis is a protein called Gasdermin-D, that perforates the plasma membrane and causes the cells to burst open.

While pyroptosis is often desired, it can also become a part of a vicious cycle in many diseases. As dying cells poke holes in their membranes, they leak molecules that cause inflammation and recruit more immune cells. This process can sometimes get out of control, causing an overactive inflammatory response that damages healthy tissues. Such chronic inflammation underlies auto-inflammatory disease, but also arthritis and IBD.

While observing cells undergoing pyroptosis the scientists found that the cells formed ‘bubbles’ of broken plasma membrane. These bubbles were then shed from cells thereby removing the damaged membrane parts and repairing the cell envelope. They also discovered that a protein complex, called ESCRT-III, was necessary to form these repair bubbles, and that when the activity of ESCRT-III was blocked, cells lost the ability to repair their membrane.

How do cells know which region of the plasma membrane is damaged? They take advantage of the fact that calcium is found in 10’000-fold higher concentrations in the extracellular milieu than inside of cells. Once the plasma membrane is perforated calcium ions rush in, like water through a broken dam, allowing cells to pinpoint where the damage has occurred and where to direct the ESCRT-III repair machinery.

Currently, Dr. Broz’s team is trying to understand the biological signals regulating ESCRT-III, to enable more precise control of this rescue machinery. These studies could eventually yield drugs to regulate the process, and thereby control pyroptosis in the context of inflammatory diseases.