The structure of a regulatory complex that is involved in metabolism and the release of cytokines has been discovered and described in a collaborative ten year study published in the journal Nature that is hoped will be employed to develop an effective treatment for lupus.
In a study that was initially investigating BRCA proteins which have been implicated in certain cancers, researchers discovered that BRCA proteins were tasked to repair damage of the DNA in these cell, but in order to achieve this the proteins had to interact with a complex of BRISC molecules. This repair sequence was noted to share similarities with the pathway of immune signaling regulation, and both shared common players.
“The important association between this complex and the immune system originally came about because my lab focuses on how BRCA1/2 function in DNA damage responses, and we realized that immune signaling entailed similar events that are governed by some of the same players involved in BRCA function.” says Roger Greenberg.
SHMT2 enzymes are a key part of DNA repair function of BRCA1, and it links to BRISC complex to regulate the immune system response; the enzyme mediates reactions which involve transfer of one carbon units to build amino acids and nucleotides essential to synthesis of proteins and DNA, in which the enzyme must couple with pyridoxine metabolites for activation.
In this decade long collaborative study cryo-electron microscopy techniques were used to reveal the blueprint for the BRISC complex, in the process of doing so the SHMT2-BRISC interaction was found to promote cytokine release from immune cells. BRISC-SHT2 complex is U shaped with 4 components each comprising a BRISC-enzyme subunit; each subunit presents a bonding site which projects from the side of the complex, and the U arms are linked by SHMT2 preventing access to the active site of the enzyme and inhibits activity, restricting BRISC activation to only act on inflammatory sites preventing immune hyperactivation under normal circumstances.
Collaborative findings from the University of Pennsylvania and colleagues from the University of Leeds led to the idea that certain drugs which bind to the complex may inhibit cytokine release and suppress autoimmune activity; thus drugs that induce mutations on SHMT2-BRISC binding sites may be targets in development of new treatments for autoimmune diseases.
The researchers plan to investigate developing compounds such as small molecule inhibitors that may inhibit BRISC activity to quiet the cytokine storm in lupus, their findings and elucidation of the structure has uncovered points at which the complex is susceptible to intervention by drugs of which they researchers hope to exploit.
“We want to find a drug targeting BRISC to decrease interferon in order to help lupus patients. Knowing the vulnerabilities in the detailed structure of the BRISC-SHMT2 complex gives us new targets to work with.” adds Greenberg.
