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 ==========================================================================
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

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230524181842.htm

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