Scientists uncover new function of a key component in the immune system

Protecting cells from stress such as high blood sugar levels may be important in treating diabetes and other diseases. 

New research findings have shown that the complement protein C3 can protect beta cells in the pancreas from stress (e.g. long-term high blood sugar levels) when diabetes is in progress.

The complement proteins that circulate in our blood are an important part of our immune system. They help identify bacteria, viruses and other harmful organisms, making it easier for our white blood cells to find and neutralise dangerous microbes.

Researchers at Lund University in Sweden working with colleagues in UCD Conway Institute have now discovered a previously unknown function of the central complement protein, C3, which describes how C3 regulates autophagy.

The miroarray experiment for C3 displays positive interactions in green surrounded by the fluorescent red guide spots. Image shown highlights one field as a subarray showing very specific binding of the fluorescent green C3 binding to specific pairs of spots.

Autophagy is the basic mechanism that controls the ability of cells to break down their own material, i.e. dispose of cellular waste, and generate new energy by reusing their own components. 

Disruption of the autophagy mechanism is thought to contribute to the development of several diseases. This new finding can play an important role in our understanding of the onset and treatment of type 2 diabetes and other diseases.

Previous work from Lund University showed that the complement system, which consists of some 40 proteins in the blood, is also present in the beta cells of the pancreas.

One protein, CD59, was shown to be essential for enabling beta cells to secrete insulin. Another protein, C3, was produced in large amounts in the beta cells, but its exact role was unclear.

Using CRISPR/Cas 9 technique to remove the gene expressing the complement protein C3 from the beta cells, the team found that autophagy was disrupted and the cells died more easily from stress. They also found that C3 production in beta cells increases considerably in response to diabetes and inflammation, probably in an attempt to protect beta cells.

Commenting on the study, Dr David O’Connell, Assistant Professor, UCD School of Biomolecular & Biomedical Science and Fellow, UCD Conway Institute said,

“As part of an ongoing collaboration, lead author Dr Ben King visited UCD Conway Institute to carry out protein microarray screening and analysis with us for a number of immune proteins associated with diabetes. The link with autophagy was then identified and further characterised after his return to the Blom laboratory in Lund. Subsequent protein interaction studies are now also underway.”

Professor Anna Blom from Lund University explains, "C3 is a very old protein from an evolutionary perspective and we have now shown that it not only has a role in the relatively modern immune system in the blood, but also within cells, where it is needed for one of the most fundamental cellular functions, autophagy.

In all likelihood, this applies to many cell types and opens the way for new principles in the treatment of diseases such as type 2 diabetes and certain neurodegenerative diseases for which there is a need to protect cells from stress.

The study is published in Cell Metabolism and available to read online at https://doi.org/10.1016/j.cmet.2018.09.009. King et al., Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents ß Cell Death via ATG16L1 Interaction and Autophagy Regulation, Cell Metabolism (2018).