Double agent

An article published in Nature with the participation of a Brazilian researcher reveals the double function of BID molecules in treating gastrointestinal illnesses

By Mônica Pileggi

Agência FAPESP – A study published in Nature magazine could be the start of curing inflammatory disease of the gastrointestinal tract, like Crohn’s disease or ulcerative colitis.

The article, whose co-author is a Brazilian researcher, describes the dual role of the BID protein, capable of modulating events favorable to and against apoptosis (programmed cellular death).

“In the process of cellular death, the BID molecule is cleaved by the caspase 8 enzyme, which activated the pro-apoptotic action of BID, prompting damage to the mitochondria which culminate in cell shrinkage and chromatin condensation, events that characterize apoptosis,” Ricardo Corrêa, senior researcher at the Sanford-Burnham Medical Research Institute, to Agência FAPESP.

Nevertheless, this new project demonstrates that in interacting with NOD1 and NOD2 (Nucleotide-binding Oligomerization Domain-containing) proteins, the BID also behaves as a regulator of immunological response, in order to allow for cellular survival.
 
“This is a modulator that simultaneously participates in yet another cellular event. Apoptosis, immune response and inflammation are events that we initially thought were unrelated, but we observed that they are intimately connected,” he said.

The human body is comprised of diverse types of molecules whose concentration is greater in the abdominal area of the gastrointestinal tract, among them NOD1 and NOD2.

This region is susceptible to chronic inflammatory disease such as ulcerative colitis and Crohn’s disease. According to Corrêa, NODs play an important role in immunological response, because they stimulate the synthesis of cytokines by activation of NF-kapaB signaling, thus helping in destruction of the invading pathogen.

“In penetrating the body’s healthy cells, bacteria – gram positive and negative – begin the infectious process.  And, in order to guarantee that cells survive infections, the NODs 1 and 2 initiate a counter-attack, activating a cascade of signals for production of cytokines and as such protect the cells,” he explains.

With a bachelor’s degree in Pharmacy-Biochemistry from Universidade de São Paulo’s (USP) Pharmaceutical Sciences College and a doctorate from USP’s Chemistry Institute (supported by a FAPESP fellowship), the researcher has been in San Diego since 2007.

Corrêa’s new study, conducted in partnership with scientists from McGill University in Canada, initially aimed to identify the potential genes for modulating NOD1 activation, whose production is associated with some inflammatory diseases in the intestine.

In the identification process, the group utilized data from an RNA interference (RNAI) library with more than 7,000  human genes. This library was used to conduct triage and data analysis to find BID, a protein that belongs to the BCL2 family. In manipulating in vitro expression of BID, scientists observed that this endogenous protein is also essential for  maintaining NOD1 and NOD2 active. “We observed that in excluding BID from the modulation process, NOD activity is affected because its action is inhibited,” highlights the Brazilians scientist.

The researchers, however, verified that depending on the degree of infection, the activation of these enzymes could play an undesired role with the cells. “In grave infections, production of cytokines ended up prolonging itself for a much longer time. This excess of protective substances can cause chronic pro-inflammatory effects,” he said. 

To promote the desired improvement in carriers of inflammatory diseases of the gastrointestinal tract, the researchers are now seeking to understand the action mechanism of BID over NOD1 and NOD2.
According to Corrêa, the group expects to produce BID in vitro and through structural biology, locate the sites of interactions that form the complex between NODs and the protein.

The article Non-apoptotic role of BID in inflammation and innate immunity (doi:10.1038/nature09982), by Ricardo Corrêa et tal can be read by Nature magazine subscribers at www.nature.com/nature/journal/v474/n7349/full/nature09982.html.