A new study out of Germany could advance the understanding of how an overactive immune system leads to the excess of inflammation that occurs in many different diseases, including psoriasis. The research report, “Phosphatidylserine exposure is required for ADAM17 sheddase function,” was published in the journal Nature Communications.
Tumor necrosis factor-alpha (TNF-α) is an immune system regulator known to be involved in many diseases in which inflammation occurs. Many different drugs block TNF-α, forming the basis of treatments for conditions including arthritis, bowel diseases, and psoriasis.
Prof. Karina Reiss, principal author of the current study, discovered crucial information about how TNF-α is involved in inflammation. She and colleagues continue to study how this molecule may be regulated.
The enzyme ADAM17 is one important molecule for determining how TNF-α works. The protease has a critical role in releasing other signalling molecules from cell surfaces and allowing them to do their job.
“The protease cuts off substrates directly via the cell membrane. Then these proteins that have now been released can bind themselves to receptors on other cells. This is how the protease ADAM17 regulates an unbelievable amount in our bodies,” explained Reiss, from the Kiel University’s Faculty of Medicine and the University Medical Center Schleswig-Holstein (UKSH).
ADAM17 releases many different types of molecules (substrates), which can control cell division, tissue growth, and the immune system.
“But no one has yet understood how this works at the molecular level. We have made an important contribution to this. For the first time we can describe the mechanism of how ADAM17 is activated and therefore make a major contribution to understanding the regulation of this important enzyme,” Reiss said.
“We have observed that negatively charged phosphatidylserine comes to the outside for a short time under certain conditions, so basically flips over. This creates a negative charge outside. ADAM17 has positive charges, which interact with this negative charge. This is the decisive mechanism to activate the protease so that it cuts something off, ” said Anselm Sommer, a post-doctoral researcher and lead author of the study.
“This is basically a new fundamental principle in cell biology, which we have discovered,” Reiss added. “It is therefore entirely possible that not only the protease ADAM17, but also the function of other proteins is influenced by this outward turning of PS.”
Now that the scientists have more information about how immune system molecules are regulated, the next step will be to advance their work into animals. Drugs that target ADAM17 and phosphatidylserine may eventually emerge as new treatments for diseases caused by an overactive immune system, such as psoriasis.