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Related Concept Videos

Delivery Pathways to the Lysosome01:36

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Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
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Lysosomes01:31

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Lysosomes are membrane-enclosed spherical sacs derived from the Golgi apparatus. The most important function of the lysosome is degrading macromolecules and biological polymers that are released during membrane trafficking events such as the secretory, endocytic, autophagic, and phagocytic pathways. The degradation is carried out by several hydrolytic enzymes active in an acidic environment of the lysosomal lumen. These acid hydrolases are involved in cellular processes such as cell signaling,...
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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
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Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
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High-throughput Measurement of Plasma Membrane Resealing Efficiency in Mammalian Cells
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How cells recognize and remove the perforated lysosome.

Keisuke Tabata1,2, Marika Saeki1,2, Tamotsu Yoshimori1,2,3

  • 1Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.

Autophagy
|November 11, 2022
PubMed
Summary

Damaged lysosomes are cleared by a process called lysophagy. A new CUL4A E3 ligase complex targets damaged lysosomes by ubiquitinating LAMP2, initiating their degradation.

Keywords:
CUL4ALAMP2lysophagylysosomal membrane damageselective autophagyubiquitination

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Macroautophagy (autophagy) is a fundamental cellular process for maintaining homeostasis.
  • Selective autophagy targets specific components, including organelles and pathogens.
  • Lysosomes, when damaged, are targeted for degradation via lysophagy, but the mechanism remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which cells target damaged lysosomes for degradation through autophagy.
  • To identify key proteins and pathways involved in the process of lysophagy.

Main Methods:

  • Proteomics analysis to identify potential protein interactions.
  • siRNA screening to validate gene functions.
  • Ubiquitination assays to assess protein modification.

Main Results:

  • A novel E3 ligase complex, involving Cullin 4A (CUL4A), was identified as a key regulator of lysophagy.
  • This CUL4A complex mediates K48-linked poly-ubiquitination of the lysosomal protein LAMP2 upon lysosomal damage.
  • The lumenal side of LAMP2 is crucial for recruiting the CUL4A complex to damaged lysosomes.

Conclusions:

  • The CUL4A E3 ligase complex plays a critical role in initiating lysosomal clearance.
  • K48-linked poly-ubiquitination of LAMP2 by this complex is essential for targeting damaged lysosomes for autophagic degradation.
  • This discovery provides new insights into the regulation of selective autophagy and cellular quality control.