MALT1 emerges as a potentially druggable target for MS
In experimental autoimmune encephalomyelitis (EAE), and perhaps in multiple sclerosis, too, T helper 17 (Th17) cells stand among the first of many balanced dominoes that, once tipped, send the system tumbling toward disease. But the cellular events that incite the tipping process remain mysterious. Now, research from neuroimmunologist Tak W. Mak and colleagues at the University of Toronto shows that a protein called MALT1 helps Th17 cells induce EAE in mice—in an unexpected way that “makes it druggable,” Mak says (Brüstle et al., 2012).
The work exemplifies a new direction for MS research, says Michael Racke, a neurologist and MS researcher at Ohio State University in Columbus: “If you look at current treatments for MS, they really are all very nonspecific.” For the most part, therapies globally inhibit certain cytokines or thwart T-cell activation altogether. If foiling a specific cell population—or even a single protein—could combat MS, Racke says, it might avoid the downsides of today’s brute-force therapies. The results suggest MALT1 could provide such a target.
Activation of the Th17 T-cell receptor triggers signaling in a pro-inflammatory pathway that turns on genes for key cytokines, their receptors, and other proteins that promote cell proliferation. MALT1 and two other proteins form a structural complex that helps kick off the pathway, whose effects on gene activity hinge on a transcription factor called NF-κB. Conventional wisdom gave MALT1 a key role in the complex, but recent work from several groups has shown that the protein, in contrast to its two partners, may be dispensable for the early steps in NF-κB signaling. Last year, a different job emerged for MALT1. It seems to be involved in later signaling steps that rely on MALT1’s enzymatic rather than structural activity.
To determine how MALT1 might contribute to EAE-related damage, Mak and his colleagues induced the disease in mice that lack the Malt1 gene. Th17 cells proliferated and assumed their identity (according to the array of early transcription factors they produced), confirming that MALT1 is not crucial for expansion of the Th17-cell population.
When the researchers looked for signs of EAE, however, they got a surprise. The mice didn’t get sick, even though the Th17 cells “strongly infiltrated the CNS,” Mak says. The team found that the cells don’t secrete interleukin 17 (IL-17) or granulocyte-macrophage colony-stimulating factor (GM-CSF), molecules that are “very important for pathogenesis,” says Brian Schaefer, a molecular immunologist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. “The cells seem to be very functionally impaired,” he adds. The IL-17 and GM-CSF messages normally recruit and activate the other immune and glial cells that deliver the damage associated with EAE. Accordingly, the brains of genetically altered mice had fewer activated macrophages and reactive astrocytes than did wild-type mice; these deficiencies might account for their failure to develop EAE.
Given that MALT1 isn’t crucial for Th17-cell early gene activation or proliferation, Mak and his team wanted to identify the molecular events that link MALT1 to IL-17 and GM-CSF production. The researchers suspected that enzymatic activity—in particular, so-called paracaspase activity, suggested by Malt1’s sequence and confirmed by recent reports—lay at the heart of this previously unappreciated role. Caspases, which share sequence homology with paracaspases, are well known for their contributions to apoptosis, the programmed cell-death pathway. But paracaspases, which regulate a growing list of biological activities, “seem functionally unrelated” to caspases, Schaefer says, and until recently, it wasn’t clear whether MALT1’s paracaspase domain performs any physiologically relevant enzymatic activity. The sequence of MALT1’s paracaspase domain “suggests it would cut other proteins,” Mak says. Last year, another group showed that MALT1 cleaves a protein called RelB, which participates in NF-κB signaling (Hailfinger et al., 2011).
The NF-κB complex acts as a first responder to various cellular stressors, from free radicals to infection to—in the case of EAE—cytokines. NF-κB describes not a particular protein but a family of transcription factor subunits. These components assemble into pairs to form NF-κB complexes, which control many genes involved in inflammation and immunity. Depending on the particular subunit makeup, they target slightly different genes. A particular molecular couple promotes the vast majority of NF-κB signaling. The MALT1 substrate RelB, it turns out, forms half of a less common signaling unit. To complicate matters, the various NF-κB subunits influence one another’s behavior, which could mean that changes in RelB levels could have major consequences for all kinds of NF-κB signaling. The protein appears in small quantities in the cytosol of wild-type Th17 cells but accumulates to high levels throughout Malt1-deficient cells grown in culture. Together, these findings suggest that Th17 cells’ ability to produce pathogenic molecules—such as IL-17 and GM-CSF—“may depend on the cleavage of RelB,” Mak says. However, Schaefer says, “they haven’t tied the pieces together” to identify RelB as the sole linchpin that links MALT1 to the cytokines. “There are probably many more substrates” for MALT1, Schaefer adds.
Regardless of how MALT1 contributes to EAE, the new results open up a possible new therapeutic avenue, Schaefer says. Many MS treatments block T-cell differentiation altogether, he says, “but this work shows there’s a completely different pathway you can think about”—one that hinges on the activity of a single enzyme, which would allow much more specific intervention.
That scenario—which presumably would knock down Th17 cells’ inflammatory capabilities—comes with significant concerns, Racke says: “T cells are responsible for mounting a response to all kinds of pathogenic invaders.” Mak says that “loss of MALT1 should not affect the pathogen-fighting capability” of the organism, because other types of T cells could pick up the slack left by incapacitated Th17 cells; the current experiments did not directly test that assertion.
Much work remains to be done, but MALT1 enzymatic activity might wind up leading to treatments that help keep people’s immune-system dominoes delicately balanced.
Key open questions
In addition to RelB, what other substrates might stand between MALT1 and production of IL-17 and GM-CSF?
- Are IL-17 and GM-CSF as detrimental in MS as they are in EAE?
- Do Th17 cells—and T cells in general—retain their ability to fight pathogens with the loss of MALT1?
What other functions might be compromised in T cells or other cell types by interfering with MALT1's enzymatic activity?