May 25, 2021

Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis

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featured discovery

Niederweis articleMichael Niederweis, Ph.D.Michael Niederweis, Ph.D., professor in the Department of Microbiology, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from the School of Medicine faculty members.

Working with first author and trainee, Tak Uday, Niederweis and Terje Dokland, Ph.D., professor in the Department of Microbiology, were published in Nature Communications for their paper “Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis.”

Niederweis says his laboratory described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis around six years ago. However, it was unknown at the time how the toxin was secreted by the bacteria.

In their paper, the team cites their discovery that toxin secretion by M. tuberculosis requires two small proteins that form pores in membranes. These results revealed a novel protein secretion mechanism in bacteria.

“Almost all the work published in this paper was done by a very talented graduate student Uday Tak, who obtained his Ph.D. in December 2020 and is now a postdoc at the University of Colorado,” Niederweis says. “His paper was chosen by the senior editor of Nature Communications as a highlight in “Microbiology and Infectious Diseases.”

UdayHeadshot articleFirst author Tak Uday, Ph.D.The team’s study on M. tuberculosis is vital for understanding TNT secretion. Moreover, it may contribute to more effective treatments for M. tuberculosis.

The School of Medicine communications staff sat down with Dr. Niederweis to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

Since our discovery of the tuberculosis necrotizing toxin, we suspected that its secretion mechanism might be novel since the toxin lacked classical signal peptides, which target proteins for export and secretion in other bacteria. It took the extraordinary efforts of Dr. Tak and has fearless approach to science to examine the highly controversial hypothesis that pore formation by the small EsxE and EsxF proteins, which are encoded in the same operon as the toxin gene, might be required for toxin secretion.

Q: What was your most unexpected finding?

Pore formation by small Esx proteins has been controversial in the TB field for two decades, because convincing proof was lacking. In addition, a recent paper published in PNAS concluded that pore formation a closely related Esx protein was an artifact of a detergent used during purification. However, Dr. Tak provided unrefutable proof of pore formation by EsxE and EsxF in our paper by combining biophysical, biochemical and genetic methods with electron microscopy. The electron microscopy work was done in collaboration with Dr. Terje Dokland at UAB.

Q: How do you feel your research will impact the science community?

Our research represents a major advancement in our understanding of protein secretion by M. tuberculosis and has important implications for many other small Esx proteins in Mtb and their homologs in Gram-positive bacteria.

This view is reflected by more than 5,000 views since 15 January 2021. Our paper is in the 96th percentile (ranked 11,098th) of the 338,211 tracked articles of a similar age in all journals and the 99th percentile (ranked 1st) of the 9 tracked articles of a similar age in Nature Communications.