Photo courtesy of IRCM
Researchers say they have uncovered a mechanism that could aid the development of therapies for lymphomas and leukemias.
The group’s research shed new light on a mechanism affecting activation-induced deaminase (AID), an enzyme that has proven crucial for immune response.
Javier Di Noia, PhD, of Institut de Recherches Cliniques de Montreal (IRCM) in Quebec, Canada, and his colleagues described this mechanism in The Journal of Experimental Medicine.
Dr Di Noia noted that, although AID is crucial for an efficient antibody response, high levels of the enzyme can have harmful effects and lead to cancer-causing mutations.
“The objective is to find the perfect level of AID activity to maximize the protection it provides to the body while reducing the risk of damage it can cause to cells,” he said.
Dr Di Noia and his colleagues previously found that heat-shock protein 90 (Hsp90) maintains the levels of AID by stabilizing it while it is still immature. In fact, they discovered that inhibiting Hsp90 significantly reduces the levels of AID in the cell.
“Through this new study, we identified another mechanism, controlled by the protein eEF1a [elongation factor eukaryotic elongation factor 1 α], that has the opposite effect,” said Stephen P. Methot, a PhD student in Dr Di Noia’s lab.
“The protein eEF1a retains AID in the cell’s cytoplasm, away from the genome. However, unlike Hsp90, it maintains AID in a ready-to-act state. We discovered that blocking the interaction between AID and eEF1a helps AID access the cell nucleus and thereby boosts AID activity. As a result, this could increase immune response and help fight infections, for instance.”
“We found the eEF1a mechanism is necessary to restrict AID activity in the cell. It acts as a buffer by allowing the cell to accumulate enough AID to be efficient but limits its activity to prevent the oncogenic or toxic effects that could result if too much AID is in continuous contact with the genome.”
The researchers also identified 2 existing drugs that can act on the eEF1a mechanism to release AID into the cell. The team said these drugs could potentially be used to boost AID activity and, thus, immune responses.
“With this discovery, we now understand mechanisms that can both reduce and increase the activity of AID by targeting different proteins,” Dr Di Noia said.
“This knowledge could eventually lead to new treatments to boost the immune system and help our aging population fight influenza, for example, as AID activity in our cells decreases with age. On the other hand, therapies could also be developed to lower toxic levels of AID in certain cancers such as B-cell lymphoma and leukemia.”
