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Lysosomes01:31

Lysosomes

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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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Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

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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.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
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Lysosomal Hydrolases01:22

Lysosomal Hydrolases

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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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Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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The Proteasome02:18

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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The Proteasome01:13

The Proteasome

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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.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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Related Experiment Video

Updated: Jan 7, 2026

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Polymeric Lysosome-Targeting Chimeras (PolyTACs): Extracellular Targeted Protein Degradation without Co-Opting

Ryan Hung-Hsun Lu1,2, Jithu Krishna1,2, Yasin Alp1,2

  • 1Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.

Journal of the American Chemical Society
|January 2, 2026
PubMed
Summary

Polymeric lysosome-targeting chimeras (PolyTACs) offer a novel approach to extracellular targeted protein degradation (eTPD). This new platform avoids lysosome-targeting receptors (LTRs), enabling degradation of various proteins for disease treatment.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Extracellular targeted protein degradation (eTPD) is a promising therapeutic strategy.
  • Current eTPD methods rely on ubiquitous lysosome-targeting receptors (LTRs).
  • Limitations exist, necessitating alternative strategies to avoid off-target degradation and expand therapeutic applications.

Purpose of the Study:

  • To develop a novel eTPD platform independent of LTRs.
  • To enable targeted degradation of both membrane-bound and soluble extracellular proteins.
  • To explore new molecular design paradigms for eTPD.

Main Methods:

  • Development of polymeric lysosome-targeting chimeras (PolyTACs), a polymer-antibody conjugate platform.
  • Investigation of PolyTACs' uptake pathway via multivalent interactions with cell surface receptors.
  • Demonstration of PolyTACs' efficacy in degrading disease-relevant membrane and soluble proteins.

Main Results:

  • PolyTACs facilitate eTPD without relying on LTRs.
  • A nonclassical uptake pathway mediated by multivalent interactions was identified.
  • Successful degradation of four disease-relevant membrane proteins and soluble extracellular proteins was achieved.
  • The platform demonstrated design and fabrication simplicity.

Conclusions:

  • PolyTACs represent a versatile platform for LTR-independent eTPD.
  • This approach broadens the scope of eTPD applications, particularly for diseases lacking suitable LTRs.
  • The simplicity and targeting capabilities of PolyTACs open new avenues for treating various diseases.