Researchers identify protein complex critical in helping control cell
death

Date:
February 18, 2022
Source:
University of South Florida (USF Health)
Summary:
A pathway critical for regulating a form of cell death known as
necroptosis has been identified. The team's preclinical findings
suggest that an inhibitor targeting this PPP13RG protein complex
can help prevent or reduce deaths and severe tissue damage from
heart attacks and other inflammation-associated diseases.



FULL STORY ==========================================================================
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.

A new preclinical study by Dr. Wang and colleagues at the University
of Texas Southwestern Medical Center identifies a protein complex
critical for regulating apoptosis and necroptosis -- known as protein phosphatase 1 regulatory subunit 3G/protein phosphatase 1 gamma (PPP1R3G/PP1g, or PPP1R3G complex). The researchers' findings suggest
that an inhibitor targeting this protein complex may help reduce or
prevent excessive necroptosis.

The study was reported Dec. 3, 2021, in Nature Communications.

"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."
Dr. Wang and colleagues conducted experiments using human cells and
a mouse model mimicking the cytokine storm seen in some patients with
severe COVID-19 infection. They applied CRISPR genome-wide screening to
analyze how cell function, in particular cell death, changes when one
gene is knocked out (inactivated).



========================================================================== 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 (PP1g) to directly remove
the inhibitory RIPK1 phosphorylations blocking RIPK1's enzyme activity
and cell death, thereby promoting apoptosis and necroptosis.

Dr. Wang uses the analogy of a car brake help explain what's happening
with the balance of cell survival and death in this study: RIPK1 is the
engine that drives the cell death machine (the car). Phosphorylation
applies the brake (stops the car) to prevent cells from dying. The car
(cell death machinery) can only move forward if RIPK1 dephosphorylation
is turned on by the PPP1R3G protein complex, which releases the brake.

"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 PP1g -- activates RIPK1 and
cell death. Furthermore, using a mouse model for "cytokine storm" in
humans, they discovered knockout mice deficient in Ppp1r3gwere 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.

Overall, the study suggests that inhibitors blocking the PPP1R3G/PP1g
pathway can help prevent or reduce deaths and severe damage from
inflammation- associated diseases, including heart disease, autoimmune disorders and COVID- 19, Dr. Wang said. His laboratory is working with
Jianfeng Cai, PhD, a professor in the USF Department of Chemistry, to
screen and identify peptide compounds that most efficiently inhibit the
PPP1R3G protein complex. They hope to pinpoint promising drug candidates
that may stop the massive destruction of cardiac muscle cells caused by
heart attacks.

The research was supported by grants from the Welch Foundation and the
National Institute of General Medical Sciences, a part of the National Institutes of Health.

========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jingchun Du, Yougui Xiang, Hua Liu, Shuzhen Liu, Ashwani Kumar, Chao
Xing, Zhigao Wang. RIPK1 dephosphorylation and kinase activation
by PPP1R3G/PP1g promote apoptosis and necroptosis. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-27367-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220218100724.htm

--- up 10 weeks, 6 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)