NOV 09, 2016 12:52 PM PST

More is Revealed About the Cellular Process of Necroptosis

WRITTEN BY: Carmen Leitch
A new report in Nature has shed some light on the process of necroptosis, a type of programmed cell death that is regulated and requires receptor-interacting serine/threonine-protein (RIP) kinases. Cell death is a normal and important physiological function common to every multicellular organism, as tissues must replace old cells with fresh new ones. A balance between cell death and regeneration is important to both recovery after injury and the healthy life of the organism. Dysfunction in that balance leads to disease, whether from excessive cell death causing tissue damage, or overproduction of cells and resultant tumors.
Proliferating keratinocytes in mice (green). /Credit: M Menacho-Márquez
It is established that necroptosis is closely linked to inflammation. All of the details of the exact causes of inflammation, however, are still not well understood. "What causes inflammation?" asked Manolis Pasparakis, Professor at the Institute for Genetics of the University of Cologne as well as the senior author of the report. "Can necroptosis be the trigger of inflammation in some cases and how is necroptosis regulated?"
RIPK1 is one kinase that is known to induce necroptosis. Pasparakis and colleagues engineered mice that did not express RIPK1 only in keratinocytes, a type of skin cell. "We expected that the lack of RIPK1 would prevent necroptosis - but we observed the opposite. Keratinocytes in these mice died by necroptosis, causing skin inflammation. This was puzzling: How could the removal of RIPK1 cause necroptosis?" commented another author of the work, Snehlata Kumari.
The researchers found that RIPK1 acts to halt the activity of another protein, ZIBP1, which causes necroptosis. If ZBP1 is taken out at the genetic level, the necroptosis and inflammation caused by a lack of RIPK1 are alleviated.
"ZBP1 was known as a sensor of DNA that contributes to immunity against some viruses, but so far it has not been implicated in inflammation," said Chun Kim, another author of the study.
To investigate how RIPK1 inhibits the activity of ZBP1, the scientists utilized CRISPR gene editing to alter a few amino acids in a specific part of the RIPK1 protein. That alteration should interfere with the ability of RIPK1 to interact with other proteins that influence necroptosis. In mice, if that alteration occurs in all cells of the animal, it will not survive after birth. When it occurs in only the skin cells of the animal, skin inflammation results. The researchers were able to demonstrate that the skin inflammation and embryonic death were due to the genetic alteration of the amino acids.
"This was a surprising result. These three amino acids of RIPK1 prevent ZBP1 from inducing necroptosis, and this is essential for mouse survival and the prevention of skin inflammation," said Juan Lin, one of the lead authors of the report.
"We made progress, but many pieces of the greater puzzle remain unclear," said Pasparakis. "ZBP1 has been known as a viral sensor, and now our results linked it to inflammation and disease. The triggers of chronic inflammation in humans are, in most cases, entirely unclear. Why does inflammation occur in a certain person at a certain moment? Bacterial and viral infections are discussed as possible triggers of chronic inflammation. In our work, we discovered the role of ZBP1 by experimentally altering RIPK1. Now we are wondering whether viruses or bacteria could activate ZBP1 to cause inflammation."
The investigators are currently working to reveal more about the process, including the exploration of a possible connection between ZBP1 and chronic inflammatory diseases that affect humans.
To learn more about necroptosis, watch the video above, a short webinar from Abcam featuring Assistant Professor Dr. Andrew Oberst of the University of Washington, or, read this Nature review on necroptosis and inflammation.
Source: AAAS/Eurekalert! via University of Cologne, Genes & Development, Nature
About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
NOV 27, 2019
Cell & Molecular Biology
NOV 27, 2019
A New Understanding of How Scars Form
Researchers have gained new insight into how the body scars, which can help scientists prevent pathological fibrosis, and initiate scarless healing....
DEC 09, 2019
Drug Discovery & Development
DEC 09, 2019
Could the diabetic drug 'metformin' extend a healthy lifespan?
The most commonly prescribed diabetic medication for the Type 2 condition is ‘Metformin’—a drug with a mysterious mechanism of action but...
JAN 04, 2020
JAN 04, 2020
Why Do Skincare Products Sometimes Cause Rashes?
Chemicals commonly found in skincare products are intended to avoid interactions with the part of the immune system responsible for triggering allergic inf...
FEB 03, 2020
FEB 03, 2020
The Switch Controlling the Stage of a Common Parasite
The parasite Toxoplasma gondii is thought to infect from one-quarter to one-third of the global population....
FEB 09, 2020
Genetics & Genomics
FEB 09, 2020
Mosquitoes are Driven to Search for Heat in the Hunt for Meals
Mosquitoes can be dangerous disease vectors, and they infect and kill hundreds of thousands of people with illnesses like dengue, malaria, and West Nile Virus....
FEB 20, 2020
Cell & Molecular Biology
FEB 20, 2020
Fresh Insights Into the Inner Membrane of the Mitochondria
Structures called mitochondria are crucial for life; these small powerhouses generate energy for cells. Scientists have now learned more about these ancient organelles....
Loading Comments...