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Related Concept Videos

Lysosomal Hydrolases01:22

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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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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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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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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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Emerging degrader technologies engaging lysosomal pathways.

Yu Ding1, Dong Xing2, Yiyan Fei3

  • 1Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, China. luboxun@fudan.edu.cn.

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Summary
This summary is machine-generated.

New degrader technologies harness the cell's natural lysosomal pathways for targeted protein degradation (TPD). This review explores autophagy-tethering compounds (ATTECs) and other lysosome-engaging degraders, expanding drug discovery options.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) offers novel therapeutic strategies.
  • Proteolysis-targeting chimera (PROTAC) technology has advanced TPD into clinical applications.
  • Emerging degrader technologies utilize alternative cellular machinery, particularly lysosomal pathways, to expand target scope.

Purpose of the Study:

  • To review and analyze autophagy-tethering compounds (ATTECs) for targeted protein degradation.
  • To discuss other lysosome-engaging degrader technologies, including AUTACs, AUTOTACs, LYTACs, and MoDE-As.
  • To summarize the current landscape and future directions of lysosomal TPD technologies.

Main Methods:

  • Literature review and analysis of ATTECs and related lysosomal degrader technologies.
  • Comparative discussion of different mechanisms for hijacking lysosomal degradation pathways.
  • Synthesis of current research findings and future outlook.

Main Results:

  • ATTECs hijack microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation.
  • Various other technologies (AUTACs, AUTOTACs, LYTACs, MoDE-As) also engage lysosomal pathways through distinct mechanisms.
  • These lysosomal approaches broaden the range of degradable protein targets beyond PROTACs.

Conclusions:

  • Lysosomal degrader technologies, including ATTECs, represent a significant expansion of TPD strategies.
  • These approaches offer new avenues for drug discovery by targeting proteins previously considered undruggable.
  • Further research is needed to fully realize the potential of these innovative degradation technologies.