November 13, 2018

Discovery suggests new route to fight infection, disease

Zhao-Qing Luo Zhao-Qing Luo

 WEST LAFAYETTE, Ind. – New research reveals how a single protein interferes with the immune system when exposed to the bacterium that causes Legionnaires' disease, findings that could have broad implications for development of medicines to fight disease and infection.

“Our immune system protects us from deadly infections, but successful pathogens have evolved many effective ways to subvert its function,” said Zhao-Qing Luo, a Purdue University professor of biological sciences and member of the Purdue Institute for Inflammation, Immunology and Infectious Diseases, who led the research. “We have revealed an intricate mechanism of how a protein from the potentially deadly pathogen Legionella pneumophila turns off the major immune regulatory protein NF-κB, which controls numerous important cellular processes. This is important because it reveals a highly effective and specific way to turn off an immune response.”

The findings are detailed in a paper recently published in the journal Nature Microbiology. The paper’s lead author is Purdue graduate student Ninghai Gan.

The researchers discovered that the bacterial enzyme MavC inhibits UBE2N, a human protein essential for the activation of NF-κB.

“The inhibition by MavC is achieved by adding a small protein called ubiquitin to a position in UNE2N critical for its activity,” Luo said. “Protein modification by ubiquitin, a process termed ubiquitination, is enormously important in immune development and disease processes. “

The research suggests a route to the development of new kinds of antibiotics.

“The bacterial enzyme found in this study is important for its ability to attack the host cells, so we can develop small molecules to inhibit is activity to achieve the goal of anti-infection,” Luo said. “Further, because the bacterial enzyme effectively and highly specifically inhibits the activity of a human protein essential for immunity activation, another potential application avenue is to use it to suppress immunity for autoimmune diseases or other hyperinflammatory conditions. The major challenge in the latter application is the delivery of the genes to the patient, but the concept has been suggested by many scientists in the field.”

The paper was co-authored by Luo; Gan; Ernesto S. Nakayasu, a researcher at the Pacific Northwest National Laboratory; and Purdue biology professor Peter J. Hollenbeck.

Ubiquitination is normally catalyzed by a three-enzyme reaction cascade. However, MavC alone is able to achieve ubiquitination, which plays an essential role in numerous important cellular processes such as immunity. Ubiquitination is frequently hijacked by pathogens to enable the spread of infection within a host, meaning the research findings could lead to future medicines against infection.

“Because of its high specificity and efficiency against UBE2N, MavC can be further developed into agents with potential therapeutic values for the regulation of NF-κB activation in disease conditions,” he said.

Future research will include work to develop high-throughput screening strategy to identify synthetic or natural compounds capable of inhibiting MavC‘s activity. Another potential application is to use the protein to test for different immune diseases.

The work aligns with Purdue's Giant Leaps celebration, acknowledging the university’s global advancements made in health, longevity and quality of life as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.

The research is funded by the National Institutes of Health. 

Writer: Emil Venere                

Source: Zhao-Qing Luo, 765-496-6697, luoz@purdue.edu


ABSTRACT

Legionella pneumophila inhibits immune signaling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N        

Ninghai Gan1, Ernesto S. Nakayasu2, Peter J. Hollenbeck1 and Zhao-Qing Luo1*

1Purdue Institute for Inflammation, Immunology and Infectious Disease and Department of Biological Sciences, Purdue University, West Lafayette, IN 47907

2Biological Science Division, Pacific Northwest National Laboratory, Richland, WA 99352

*Correspondence: luoz@purdue.edu 

The bacterial pathogen Legionella pneumophila modulates host immunity using effectors translocated by its Dot/Icm transporter to facilitate its intracellular replication. A number of these effectors employ diverse mechanisms to interfere with protein ubiquitination, a posttranslational modification essential for immunity. Here we found that L. pneumophila induces monoubiquitination of the E2 enzyme UBE2N by its Dot/Icm substrate MavC(Lpg2147). We demonstrate that MavC is a transglutaminase that catalyzes covalent linkage of ubiquitin to Lys92 and Lys94 of UBE2N via Gln40. Similar to canonical transglutaminases, MavC possess deamidase activity that targets ubiquitin at Gln40. We identified Cys74 as the catalytic residue for both ubiquitination and deamidation activities. Furthermore, ubiquitination of UBE2N by MavC abolishes its activity in the formation of K63-type polyubiquitin chains, which dampens NFkB signaling in the initial phase of bacterial infection. Our results reveal an unprecedented mechanism of modulating host immunity by modifying a key ubiquitination enzyme by ubiquitin transglutamination.


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