Xinhe Bio Contributes to Discovery of Novel Immune Regulatory Mechanism Against Yersinia Infection

*Yersinia* is a genus of Gram-negative bacteria widely distributed in nature. Several species within this genus exhibit extremely high virulence in humans, among which *Yersinia pestis* is the causative agent of plague, a severe infectious disease. The plague bacillus multiplies rapidly within the esophagus of fleas, obstructing the digestive tract and impeding feeding. Driven by extreme hunger, these fleas bite indiscriminately, facilitating the rapid global spread of the pathogen through their primary hosts, marmots and brown rats. Without effective treatment, infected individuals typically succumb to the disease within seven days of symptom onset. Widespread subcutaneous hemorrhaging causes the skin to turn black, giving rise to the name "Black Death" (the term also encapsulates the profound dread, despair, and mortality historically associated with the disease). Plague has caused multiple pandemics throughout human history, devastating medieval Europe and claiming approximately half of its population. For example, at the University of Oxford at the time, out of 30,000 faculty and students, only slightly over 6,000 survived one year after the pandemic began.

Pyroptosis is a novel form of programmed cell death induced by membrane pore formation mediated by Gasdermin family proteins. It serves as one of the primary mechanisms by which the host immune system defends against pathogenic invasion and has emerged as a major research hotspot in the fields of innate immunity and tumor immunotherapy in recent years.

In June 2021, Dr. Yi Wang, Co-founder and CEO of NeoCura, and Dr. Youdong Pan, Chief Scientific Officer, participated in a study published as a Research Article in *Science*, which reported the identification of the Rag-Ragulator complex as a key factor mediating *Yersinia* infection and triggering pyroptosis through CRISPR/Cas9 genome-wide knockout screening, and elucidated the molecular mechanism by which this complex activates FADD-RIPK1-Caspase-8 (complex II).

Rag-Ragulator is a key regulator of systemic nutrient metabolism and signal transduction, responsible for controlling cellular nutrient uptake and metabolism. Acting as a central hub, Rag-Ragulator monitors metabolic status and regulates nutrient availability to sustain cell growth and proliferation. In this study, researchers employed a CRISPR/Cas9 genome-wide knockout screen to demonstrate, for the first time, that the Rag-Ragulator complex (comprising RagA, RagC, and Lamtor1-5) participates in regulating Yersinia infection-induced pyroptosis. The results revealed that the Rag-Ragulator complex is specifically involved in pyroptosis mediated by the TLR/TNF-caspase-8-GSDMD pathway. Furthermore, the researchers conducted a comprehensive, multi-dimensional investigation to elucidate the precise molecular mechanisms underlying the regulatory functions of the Rag-Ragulator complex.

Taken together, this study reveals for the first time a novel function of the lysosome-localized Rag-Ragulator complex in Yersinia infection, and comprehensively elucidates the molecular mechanism of RIPK1/caspase-8 activation in host cells following infection. This work represents a significant advancement in the fields of pyroptosis and immunology, and provides new therapeutic targets and novel strategies for the treatment of diseases associated with Yersinia infections, such as Yersinia pestis and Yersinia enterocolitica.

Original link:Science | NeoCura R&D Team Contributes to Uncovering a Novel Immune Regulatory Mechanism Against Yersinia Infection

Responsible Editor: Bai Ji