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Quantifying Subcellular Ubiquitin-proteasome Activity in the Rodent Brain
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Regulación del proteasoma mediante la ribosilación por ADP-ribosilación
Park F Cho-Park1, Hermann Steller
1Strang Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Cell
|April 30, 2013
Resumen
La ADP-ribosilación mejora la actividad del proteosoma 26S mediante la modificación de PI31, un regulador. Este proceso involucra a la tanquirasas (TNKS) y promueve el ensamblaje del proteosoma 26S, crucial para la supervivencia celular y vinculado a las enfermedades.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- El sistema ubiquitina-proteasoma (UPS) es vital para la homeostasis celular, degradando las proteínas ubiquitinadas.
- Las disfunciones en el UPS están implicadas en enfermedades como el cáncer y los trastornos neurodegenerativos.
- El proteosoma 26S es la principal máquina proteolítica dentro del UPS.
Objetivo del estudio:
- Para investigar el papel de la ADP-ribosilación en la regulación de la actividad del proteosoma 26S.
- Para identificar los actores moleculares involucrados en este mecanismo de regulación.
- Explorar posibles dianas terapéuticas para enfermedades asociadas con la disfunción del proteasoma.
Principales métodos:
- Utilizó Drosophila y líneas celulares humanas.
- Interacciones proteína-proteína identificadas utilizando ensayos de coinmunoprecipitación y de unión.
- Actividad y ensamblaje evaluados del proteasoma.
- Utilizó interferencia de ARN (RNAi) y inhibidores de moléculas pequeñas (XAV939) para modular la actividad de tanquirasas (TNKS).
Principales resultados:
- Se encontró que la ADP-ribosilación promueve la actividad del proteasoma 26S tanto en Drosophila como en células humanas.
- Tankyrase (TNKS) y 19S chaperones de ensamblaje (dp27, dS5b) fueron identificados como socios de unión directa de PI31.
- La ribosilación ADP-mediada por TNKS de PI31 redujo su afinidad por el proteosoma 20S, aliviando la inhibición.
- La modificación de PI31 también promovió el ensamblaje de 26S al secuestrar dp27 y dS5b.
Conclusiones:
- La ribosilación de ADP por TNKS es un nuevo mecanismo para regular el ensamblaje y la actividad del proteosoma 26S.
- Dirigirse a las TNKS con inhibidores como XAV939 puede modular la función del proteosoma.
- Esta vía reguladora ofrece estrategias terapéuticas potenciales para enfermedades relacionadas con la disfunción del proteasoma.
Videos de Conceptos Relacionados
01:13The Proteasome
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 (ubiquitin...
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 (ubiquitin...
02:18The Proteasome
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...
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...
02:18The Proteasome
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...
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...
02:58Regulated Protein Degradation
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...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:58Regulated Protein Degradation
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...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.