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   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    A look into the heart of cellular waste disposal    
    Researchers reveal how a nanomachine takes care of cleaning up inside the   
   cell    
      
     Date:   
         May 24, 2023   
     Source:   
         Max-Planck-Gesellschaft   
     Summary:   
         Researchers reveal how a nanomachine takes care of cleaning up   
         inside the cell.   
      
      
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   FULL STORY   
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   To prevent our body's cells from overflowing with garbage and to   
   keep them healthy, the waste inside them is constantly being disposed   
   of. This cleaning process is called autophagy. Scientists have now,   
   for the first time, rebuilt the complex nanomachine in the laboratory   
   that starts this process -- and it works quite differently from other   
   cellular machines. The researchers' new insights could help open up   
   new approaches for the treatment of cancer, immune disorders, and   
   neurodegenerative diseases in the future, and possibly even delay aging.   
      
   Have you ever put off cleaning the house or decluttering the overflowing   
   basement? Living cells cannot afford this procrastination when it comes   
   to clearing the decks. Tiny garbage chutes are constantly active there   
   to capture worn-out proteins, faulty cell components, or defective   
   organelles. These garbage chutes, called autophagosomes, pick out   
   the discarded components before they accumulate in the cell and cause   
   damage. The cellular waste is then passed on to the cell's own recycling   
   machinery, the lysosome, where it is digested and recycled. Thus,   
   building blocks for new cellular components are quickly available   
   again. The autophagy process, literally self-eating, thus also helps   
   cells to survive stress or periods of starvation.   
      
   Autophagy also serves another important purpose. It renders harmless   
   viruses and bacteria that successfully bypass the immune system's defenses   
   and reach the cell plasma. The consequences are correspondingly fatal if   
   the autophagy process is faulty, too slow, or too fast. Neurodegenerative   
   diseases and cancer can develop or disorders of the immune system may   
   occur. Aging processes also appear to accelerate.   
      
   "Autophagy is a highly complex process involving many different   
   proteins and protein complexes. We know many of them, but there are   
   still fundamental gaps in our knowledge," reports Alex Faesen, research   
   group leader at the Max Planck Institute for Multidisciplinary Sciences   
   in Go"ttingen. "How do the protein components work together? How is   
   the process of autophagy started and stopped?  When and where is the   
   autophagosome assembled? That is what we want to find out."  Nanomachine   
   at work His team has now succeeded, for the first time, in producing   
   all the proteins involved in the autophagy process in the laboratory   
   and observing them directly as the autophagosomes assemble. This was   
   a mammoth task for the entire research group, taking several years,   
   for which they cooperated with the teams led by Bjo"rn Stork from   
   the University of Du"sseldorf and Michael Meinecke, previously at the   
   University Medical Center Go"ttingen now at the Heidelberg University   
   Biochemistry Center. "There were many challenges," recalls Faesen.   
      
   In the first step, the scientists produced each individual protein   
   component in the laboratory. The standard approach is to use bacteria   
   that are genetically reprogrammed to produce the desired protein in large   
   quantities. "But protein production with bacteria did not work for any of   
   our proteins," the Go"ttingen biochemist says. Instead, the researchers   
   switched to insect cells as molecular helpers -- the breakthrough.   
      
   In the next step, the team brought the individual protein complexes   
   together.   
      
   "The complexes self-assembled into a protein supercomplex, the autophagy   
   initiation complex. In fact, autophagy involves a sophisticated cellular   
   nanomachine -- and it works quite differently than previously thought,"   
   the group leader says.   
      
   To make autophagosomes, the autophagy initiation complex first creates   
   a junction between a particular structure of the cell, the endoplasmic   
   reticulum, and the autophagosome that forms. Under stress or in times of   
   starvation, such as during endurance sports, this occurs within just a   
   few minutes. "From this point on, there is no turning back: The waste   
   disposal is assembled and collects the cellular waste," explains Anh   
   Nguyen, one of the two first authors of the study. Co-first author   
   Fancesca Lugarini adds, "Via the contact site, fat-like molecules   
   called lipids are transported to a precursor stage of autophagosomes,   
   where they are incorporated." These grow and, in the process, enclose   
   the cell material to be disposed of -- the finished mini-organelle is   
   formed. Within barely 20 minutes of its formation, the autophagosome is   
   already delivering its waste to the lysosome by fusing with it.   
      
   Protein origami for "on" and "off" But what starts the assembly of the   
   autophagy machine, what starts it and what stops it? The researchers   
   did not find a molecular "on" and "off" switch as in other molecular   
   machines. Instead, the switch uses a highly unusual behavior of proteins:   
   metamorphosis. " Certain molecules, called ATG13 and ATG101, have the   
   ability to fold in different 3D structures, thereby changing its ability   
   to bind to proteins in the machine. "This protein metamorphosis also   
   gives the go- ahead for the assembly of the autophagy initiation complex   
   at the right time and in the right place," says Faesen, describing the   
   special features of the nanomachine. Without metamorphosis, the initiation   
   machine does not assemble.   
      
   The scientists hope that the new findings will advance the development   
   of future drugs that can be used to treat diseases that are based on a   
   faulty autophagy process.   
      
       * RELATED_TOPICS   
             o Plants_&_Animals   
                   # Cell_Biology # Molecular_Biology #   
                   Biotechnology_and_Bioengineering # Genetics #   
                   Biotechnology # Biology # Biochemistry_Research #   
                   Developmental_Biology   
       * RELATED_TERMS   
             o Cell_membrane o Gas_exchange o T_cell o Necrosis   
             o Autophagy o Maggot_therapy o Natural_killer_cell o   
             Somatic_cell_nuclear_transfer   
      
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   Story Source: Materials provided by Max-Planck-Gesellschaft. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Anh Nguyen, Francesca Lugarini, Ce'line David, Pouya Hosnani,   
      C,ağla   
         Alago"z, Annabelle Friedrich, David Schlu"termann, Barbora Knotkova,   
         Anoshi Patel, Iwan Parfentev, Henning Urlaub, Michael Meinecke,   
         Bjo"rn Stork, Alex C. Faesen. Metamorphic proteins at the basis   
         of human autophagy initiation and lipid transfer. Molecular Cell,   
         2023; DOI: 10.1016/j.molcel.2023.04.026   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230524181842.htm   
      
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