MSGID: 1:317/3 642661eb   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Form is (mal)function: Protein's shape lets bacteria disarm it    
    Researchers show a crucial protein of the innate immune system has six   
   different forms, and probably many different roles in the body    
      
     Date:   
         March 30, 2023   
     Source:   
         University of Connecticut   
     Summary:   
         Shigella bacteria can infect humans but not mice. A team can now   
         explain why. Their findings may explain the multifariousness of   
         a key weapon of our immune system.   
      
      
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   FULL STORY   
   ==========================================================================   
   Shigella bacteria can infect humans but not mice. In the March 29 issue   
   ofNature, a team from UConn Health explains why. Their findings may   
   explain the multifariousness of a key weapon of our immune system.   
      
      
   ==========================================================================   
   Shigella infections cause fever, stomach pain, and prolonged, sometimes   
   bloody diarrhea for as long as a week. The bacteria sicken 450,000   
   people each year in the US alone. Although most people recover on their   
   own, children and those with weakened immune systems are at risk of   
   Shigella infections spreading to their bloodstream and causing kidney   
   damage. Shigella infections are a significant cause of sickness and   
   disability, but it's difficult to study the bacteria because it only   
   sickens primates like humans and apes -- not animals easy to study in   
   a lab. The bacteria cannot infect more typical lab animals such as mice.   
      
   Previous research had looked at how Shigella interacts with gasdermin-B,   
   a critical part of our immune system that helps protect us against   
   infection.   
      
   Gasdermin-B is member of a protein family called gasdermin, which includes   
   gasdermin-A, -B, -C, -D, -E and -F. It was thought that when gasdermin-   
   B detects an invader, such as bacteria, it begins to poke holes in the   
   cell's wall, causing it to burst open and release chemicals that induce   
   inflammation and call reinforcements from the immune system. But the   
   past research studies on gasdermin-B were contradictory; some confirmed   
   its role in cell death during infection, but others contradicted the idea.   
      
   UConn School of Medicine immunologist Jianbin Ruan and a team of   
   colleagues from UConn Health wanted to clarify whether gasdermin-B   
   actually does cause cell death in the case of microbial invasion;   
   they also wanted to figure out why it doesn't do this when Shigella is   
   the invader.   
      
   The team needed to take a close look at gasdermin-B. They expressed   
   the protein, purified it, and then cooled the protein down to very low   
   temperatures so it would hold still while they took pictures of it with   
   an electron microscope.   
      
   "We collected hundreds of thousands of images to build the 3D models   
   of protein molecules at the atomic level. Through these models we will   
   understand what these proteins look like and how they do their job,"   
   said Chengliang Wang, research fellow in the Ruan lab and first author   
   of the study.   
      
   Their research confirms previous research and provides evidence   
   that Shigella bacteria grab onto a specific segment of gasdermin-B in   
   humans. However, the mouse version of the protein has a different shape   
   that prevents Shigella from latching onto it, resulting in the rapid   
   clearance of the bacteria and preventing infection. This finding helps   
   explain why Shigella is unable to infect mice.   
      
   Since human gasdermin-B can be configured in six slightly differing   
   proteins, or isoforms, the team expressed all six then looked at how   
   these isoforms behaved inside cells, and they found something surprising:   
   some of the isoforms of gasdermin-B did indeed poke holes to cause cell   
   death -- but other isoforms did not.   
      
   "Previously, people didn't understand why studies contradicted each   
   other. We show that only two of the isoforms of gasdermin-B cause   
   pyroptosis, or cell death," says Ruan. Those two isoforms contain a   
   specific protein segment that is absent in the other gasdermin-B isoforms,   
   as shown by their cryogenic electron microscopy structure.   
      
   The finding may explain many mysteries of cell death, and life. Cancer   
   cells, for example, are notoriously long lived and unlikely to die via   
   pyroptosis. It may be that these cancer cells express only gasdermin-B   
   isoforms that don't poke holes in cell walls.   
      
   However, we don't yet know what these other isoforms are doing. It   
   may be that the different isoforms of gasdermin-B play significant and   
   distinctive roles depending on where they are in the body, and different   
   cell types preferentially express different isoforms.   
      
   "The protein structures that our team discovered have significant   
   implications for drug development. Specifically, they can inform the   
   design of small molecule drugs that modulate gasdermin-B activity,"   
   explains Ruan. "These drugs could potentially be used to treat a range   
   of conditions, including cancer, inflammatory and autoimmune diseases,   
   and infectious diseases by either suppressing or enhancing the immune   
   response. Our findings thus hold promise for the development of novel   
   therapies to address these pressing medical needs."   
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Immune_System # Lymphoma # Diseases_and_Conditions #   
                   Human_Biology   
             o Plants_&_Animals   
                   # Molecular_Biology # Cell_Biology # Biotechnology #   
                   Biotechnology_and_Bioengineering   
       * RELATED_TERMS   
             o Immune_system o Transplant_rejection o House_mouse o Pathogen   
             o Visual_perception o Biological_warfare o Mouse o Lymphoma   
      
   ==========================================================================   
   Story Source: Materials provided by University_of_Connecticut. Original   
   written by Kim Krieger. Note: Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Chengliang Wang, Sonia Shivcharan, Tian Tian, Skylar Wright,   
      Danyang Ma,   
         JengYih Chang, Kunpeng Li, Kangkang Song, Chen Xu, Vijay   
         A. Rathinam, Jianbin Ruan. Structural basis for GSDMB pore   
         formation and its targeting by IpaH7.8. Nature, 2023; DOI:   
         10.1038/s41586-023-05832-z   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230330172215.htm   
      
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