Nature reveals a new mechanism by which pathogenic bacteria evade natural immunity

Since childhood, we know that we should pay attention to hygiene and avoid "disease from the mouth", because many bacteria in nature, once the human immune defense, may cause disease. Shigella, for example, is a common cause of diarrhea. Shigella, also known as dysentery bacillus, can cause bacterial dysentery when it enters the body through contaminated food or water, resulting in bloody diarrhea and severe intestinal inflammation.

Understanding how disease-causing bacteria infect host cells and how host cells defend against disease-causing bacteria is fundamental to providing ways to prevent and treat disease.

In the field of natural immunity against bacteria, Dr. Shao Feng of the Beijing Institute of Life Sciences has made many important discoveries over the years, pointing out that after bacteria invade host cells, cells cause antibacterial inflammatory reactions through a death process called pyroptosis.

Recently, Dr. Shao feng and Dr. Xiaoyun Liu of Peking University School of Basic Medical Sciences published an important new progress in the leading academic journal Nature, revealing a new mechanism by which pathogenic bacteria inhibit pyrodeath in host cells. This discovery adds another milestone in the field of pathogen and host cell interaction.

In previous studies, Dr. Shao et al found that after pathogen invasion, the caspase family of proteases in host cells is activated by lipopolysaccharide (LPS, commonly known as endotoxin), a key component of the bacterial membrane, and then cleaves the key protein GSDMD, causing it to perforate the cell membrane, ultimately inducing cell pyrodeath.

However, pathogenic bacteria and host cells are constantly fighting each other for their own survival. Some pathogens have developed the ability to inhibit the function of cystease over a long period of evolution.

The team found that the cellular caspase-11 protein did not protect mice from Shigella flexneri infection, although it plays a key role in the process of caustic pyrophosis. Further in vitro cell experiments suggested that Shigella could escape cell pyroapoptosis mediated by caspase-11-GSDMD pathway through a certain pathway.

After screening for several effector molecules that shigella may use to inhibit the caspase signaling pathway, we identified the effector protein OspC3 secreted by shigella as a possible weapon in their ability to escape by inhibiting LPS-induced scortosis.

As they continued to explore how OspC3 inhibits caspase function, the researchers found something unexpected. Although OspC3 can bind to caspase-11, this simple binding is not enough to inhibit it. A series of biochemical experiments and mass spectrometry showed that a special "post-translational modification" of caspase protein occurred in the presence of OspC3.

Specifically, this post-translational modification at first glance looks similar to adP-ribosylation, which has been known for decades, using NAD+ molecules as donors to modify proteins, but the resulting molecular weight changes are mind-bogglingly small. The researchers did not miss this difference, and through isotope labeling combined with mass spectrometry and other methods, finally found that OspC3 mediated a novel protein post-translational modification process, which is one step more than adP-riboylation process, they named it ADP-Riboxanation.

Researchers have discovered a novel post-translational modification of proteins: ADP-riboxanation

In this paper, we demonstrate that when AdP-riboxanation occurs in caspase-11, the automatic processing, recognition and cleavage of GSDMD are no longer possible, resulting in the failure of the natural immunity mediated by cell burn death.

Thus, the team solved the mystery of how the pathogen shigella escaped natural immunity. Of course, the detailed explanation of the mechanism has also led to potential strategies against pathogens.