New research suggests there are 4 different “locks” that keep the CARD11 protein in check.
Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.
But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.
Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.1,2
The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.
To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.
Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.
They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.
To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.
In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.
“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”
So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.
Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.
“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.
According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.
“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”
