Biological complexity: cell death controls (Introduction)

by David Turell , Monday, February 21, 2022, 16:00 (1006 days ago) @ David Turell

Cells must die, but in controlled amounts:

https://www.sciencedaily.com/releases/2022/02/220218100724.htm

"Cell death plays an important role in normal human development and health but requires tightly orchestrated balance to avert disease. Too much can trigger a massive inflammatory immune response that damages tissues and organs. Not enough can interfere with the body's ability to fight infection or lead to cancer.

"Zhigao Wang, PhD, associate professor of cardiovascular sciences at the University of South Florida Health (USF Health) Morsani College of Medicine, studies the complex molecular processes underlying necroptosis, which combines characteristics of apoptosis (regulated or programmed cell death) and necrosis (unregulated cell death).

"During necroptosis dying cells rupture and release their contents. This sends out alarm signals to the immune system, triggering immune cells to fight infection or limit injury. Excessive necroptosis can be a problem in some diseases like stroke or heart attack, when cells die from inadequate blood supply, or in severe COVID-19, when an extreme response to infection causes organ damage or even death.

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"'Cell death is very complicated process, which requires layers upon layers of brakes to prevent too many cells from dying," said study principal investigator Dr. Wang, a member of the USF Health Heart Institute. "If you want to protect cells from excessive death, then the protein complex we identified in this study is one of many steps you must control."

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"Receptor-interacting protein kinase (RIPK1) plays a critical role in regulating inflammation and cell death. Many sites on this protein are modified when a phosphate is added (a process known as phosphorylation) to suppress RIPK1's cell death-promoting enzyme activity. How the phosphate is removed from RIPK1 sites (dephosphorylation) to restore cell death is poorly understood. Dr. Wang and colleagues discovered that PPP1R3G recruits phosphatase 1 gamma (PP1γ) to directly remove the inhibitory RIPK1 phosphorylations blocking RIPK1's enzyme activity and cell death, thereby promoting apoptosis and necroptosis.

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"'In this case, phosphorylation inhibits the cell death function of protein RIPK1, so more cells survive," he said. "Dephosphorylation takes away the inhibition, allowing RIPK1 to activate its cell death function."

"The researchers showed that a specific protein-protein interaction -- that is, PPP1R3G binding to PP1γ -- activates RIPK1 and cell death. Furthermore, using a mouse model for "cytokine storm" in humans, they discovered knockout mice deficient in Ppp1r3g were protected against tumor necrosis factor-induced systemic inflammatory response syndrome. These knockout mice had significantly less tissue damage and a much better survival rate than wildtype mice with the same TNF-induced inflammatory syndrome and all their genes intact."

Comment: the need for such precise controls implies it has to be a designed mechanism, as it is irreducibly complex.