Unlocking a microbial puzzle to better treat, prevent, and detect disease

Many medications and other therapeutic agents, including antibiotics and cancer therapies, must enter cells to reach their targets to have their effect. But that can pose a challenge, as drugs often have difficulty crossing the cell’s protective membranes, get broken down before they reach their target, or do not reach the right cells.

Lipoproteins, a type of lipid-anchored surface protein, contain a protein motif or sequence called a lipobox, explains fifth-year biology Ph.D. student Yurui Hong. This sequence serves as a signal for enzymes that carry out lipidation, the process of anchoring lipids to proteins.

“Think about lipobox as a lock,” Hong says. “Bacteria have a very special key to open that lock, and archaea also have the same lock, but you cannot use the same key to open that lock, suggesting archaea must have some special mechanism to develop their own key.”

Scientists have known for 30 years that the lock in archaea exists but haven’t been able to identify the key, Hong says. Now, she led a study identifying the key: two enzymes—called AliA and AliB—responsible for anchoring lipoproteins to membrane lipids in archaea. The paper is published in Nature Communications.

“We can use this information to learn more about the basic cell biology of archaea but also to then hopefully translate that into potential biotechnological applications,” says senior author Mecky Pohlschröder, professor of biology in the School of Arts & Sciences.

That’s because archaeal lipids form the building blocks of archaesomes, vesicles with great potential for drug delivery, vaccines, and cancer diagnostics. Hong explains that unlike their equivalent in bacteria, archaesomes are more stable—meaning they don’t degrade as quickly in extreme environments, such as the human stomach.

“By uncovering how surface proteins are lipid-anchored, this study paves the way for engineering archaesomes with tailored surface molecules—such as antibodies or antigens—for precise targeting of specific cells, tissues, or organs,” Pohlschröder says.

The researchers also confirmed that lipoproteins are abundant across archaea, and they found that AliA and AliB are important for the growth, cell shape, and motility of the model species of archaea they studied, Hfx. Volcanii. 

She says that Hong’s bioinformatic analysis identified other proteins that might be involved in the archaeal lipoprotein biogenesis pathway, making that a next step for future research.

Another direction for future research, Pohlschröder says, is teasing apart the different functions of AliA and AliB and their interplay—a new layer of regulation in lipoprotein biogenesis that is unprecedented in both archaea and bacteria.

Mecky Pohlschröder is a professor in the Department of Biology in the School of Arts & Sciences at the University of Pennsylvania.

Yirui Hong is a fifth-year microbiology Ph.D. candidate in the Pohlschröder Lab. 

The other co-authors are Rachel Xu of Penn’s Department of Biology, Friedhelm Pfeiffer of the Max Planck Institute of Biochemistry, Kira S. Makarova of the National Institutes of Health, and Andy A. Garcia and Paula V. Welander of Stanford University. 

This research was supported by the National Science Foundation (grants MBC-2222076 and EAR-1752564), intramural funds of the U.S. Department of Health and Human Services (National Institutes of Health and National Library of Medicine), University of Pennsylvania Research Fund, and Teece Dissertation Research Award at the University of Pennsylvania.