After a plant has detected and destroyed invading bacteria, its innate immune system must be turned off to prevent a prolonged immune response from damaging the plant's tissues. This downregulation of the immune system in Arabidopsis falls on the shoulders of two novel proteins that target and degrade innate immune receptors after an infection, according to a study published this week in Science.
The mechanism, which has direct parallels in human immune signaling pathways, offers basic insights that might someday help to develop therapeutics against autoimmune diseases, which arise from an overactive immune response.
"It's a beautiful piece of biology," said Luke O'Neill, an immunologist at Trinity College in Dublin, who was not involved in the research. "It's intriguing that the same system is used in humans, so it must be very important for life."
The Arabidopsis flagellin-sensing receptor 2 (FLS2) is one of the best-studied innate immune receptors in plants. The receptor senses flagellin, proteins that form a bacterium's tail, and activates the innate immune response through a kinase called BAK1. Libo Shan and colleagues at Texas A&M University used BAK1 as bait to see what other molecules are involved in FLS2 signaling. In yeast, they discovered that BAK1 binds two ubiquitin ligases -- proteins that attach ubiquitin tags to other proteins, usually to target them for degradation.
To determine the function of these ubiquitin ligases, called PUB12 and PUB13, the team made mutant plants lacking the two proteins. They were surprised to find that the mutants had elevated immune responses to flagellin exposure: they were 5 to 10 times more resistant to bacterial infection than wild-type plants. PUB12 and PUB13, it turns out, play a negative role in innate immune signaling. When they are phosphorylated and activated by BAK1, the ligases tag FLS2 for degradation, leading to a weakening of and eventual end to the innate immune response.
"After the immune response, these proteins come and tune down that response in order to avoid deleterious, constitutive activation of the immune system," said Shan. "It provides a mechanism of how a host regulates an immune response perfectly and on time."
The elevated immune response in the mutant plants could help scientists develop ways to genetically manipulate crops to boost their diseases resistance, the authors write. But the finding may also be pertinent for human health because our cells use a similar mechanism to detect bacterial invasion. When activated by a bacterial protein, Toll-like receptor 4 (TLR4) in humans rapidly phosphorylates a downstream kinase, just as FLS2 phosphorylates BAK1, to activate an innate immune response. Later, a downstream enzyme tags TLR4 for degradation, just as PUB12 and PUB13 mark FLS2 for the cellular trashcan. In humans, however, it is not known how that enzyme is activated to degrade TLR4.
Using the insights provided by the role of BAK1 in activating PUB12 and PUB13,"we may be able to find, by analogy, undiscovered components in the human system," said O'Neill, who wrote an accompanying Perspective in Science. These missing components could prove to be clinically valuable, as TLR4 has been implicated in numerous autoimmune diseases such as rheumatoid arthritis and atherosclerosis.
D. Lu, et al., “Direct ubiquitination of pattern recognition receptor FLS2 attenuates plant innate immunity,” Science, 332:1439-42, 2011.