This study aims to prove 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 signalling entailed similar events; that are governed by some of the same players involved in BRCA function.
In the systemic process serine hydroxymethyltransferase 2 regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism; and uses pyridoxal-5′-phosphate as a cofactor. But the full length SHMT2 localizes to mitochondria through an N-terminal mitochondrion-targeting sequence.
Hence, some N-terminal truncation that removes residues 1–21 generates the cytoplasmic SHMT2α isoform PLP, the active form of vitamin B6; promotes a shift in the SHMT2 oligomeric state from an inactive dimer to the enzymatically active tetramer. An enzyme that functions with BRCA1 to repair damaged DNA also exists within a separate complex called BRISC to regulate immune signalling.
Immune System Diseases
Greenberg’s team explored the relationship between BRISC and immune cell surface receptors to better understand the symptoms of lupus and other autoimmune diseases. The overproduction of immune cells, and their signaling compounds called cytokines; stirs up hyper-inflammation that can cause substantial tissue damage, an effect of many autoimmune disorders.
But in some lupus patients, in particular, produce too much of the cytokine interferon, a natural chemical that signals to the immune system in ways that can exacerbate inflammation; Their findings revealed a fascinating molecular mechanism that connected BRISC to an enzyme involved in metabolism called serine hydroxymethyltransferase 2 (SHMT2).
Kinetic data suggest SHMT2 acts as an apparent competitive inhibitor. However, the increase in Km was only moderate chains might displace bound SHMT2 from BRISC; when polyubiquitylated substrates are in close proximity; This model would account for the counterintuitive function of SHMT2 as both an inhibitor of BRISC activity and an essential mediator of BRISC association with sites of DUB action.
SHMT2 guides reactions essential for basic body functions, such as building blocks for proteins and DNA; after being activated by a form of vitamin B6; These data suggest a previously unknown role for the dimeric (PLP-free) form of SHMT2 in regulating the DUB activity of BRISC; By these data the study revealing the mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.