Video Experimental Relacionado
Updated: Jul 17, 2026
06:06
In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
La ubiquitinación inducida por ligandos desencadena la función del punto de control inmune LAG3 al impedir el
Yong Jiang1, Anran Dai2, Yuwei Huang3
1School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Cell
|March 18, 2025
Resumen
El gen de activación linfocítica 3 (LAG3) se activa por poliubiquitinación no vinculada a K48 tras la unión con el ligando, lo que mejora su supresión inmune. Este mecanismo, dirigido por anticuerpos terapéuticos, ofrece nuevas estrategias de inmunoterapia contra el cáncer.
Área de la Ciencia:
- Inmunología
- Biología molecular
- Investigación del cáncer
Sus antecedentes:
- El gen de activación linfocítica 3 (LAG3) es un objetivo clave del punto de control inmunológico en la inmunoterapia contra el cáncer.
- El mecanismo preciso de activación de LAG3 después de la interacción con el ligando no está claro.
Objetivo del estudio:
- Para aclarar el mecanismo molecular de la activación de LAG3 en la unión del ligando.
- Investigar el papel de la ubiquitinación en la función de LAG3 y sus implicaciones para la inmunoterapia del cáncer.
Principales métodos:
- Se estudió la ubiquitinación de LAG3 utilizando ensayos bioquímicos y modelos basados en células.
- Se investigó el papel de las ligasas E3 c-Cbl y Cbl-b en la ubiquitinación de LAG3.
- Se analizó el impacto de la ubiquitinación de LAG3 en la inmunidad antitumoral in vivo.
- Efectos terapéuticos correlacionados con los niveles de ubiquitinación de LAG3.
Principales resultados:
- El compromiso de ligandos desencadena la poliubiquitinación no vinculada a K48 de LAG3, mejorando su función inhibidora.
- El complejo mayor de histocompatibilidad clase II (MHC clase II) y la proteína tipo fibrinógeno unida a la membrana 1 (FGL1) inducen la ubiquitinación de LAG3.
- La ubiquitinación, mediada por c-Cbl y Cbl-b, estabiliza la cola citoplasmática de LAG3, promoviendo la señalización.
- La ubiquitinación de LAG3 es esencial para suprimir la inmunidad antitumoral in vivo.
- Los anticuerpos LAG3 terapéuticos inhiben la ubiquitinación de LAG3, lo que se correlaciona con la eficacia del bloqueo del punto de control.
Conclusiones:
- La activación de LAG3 implica la poliubiquitinación no ligada a K48, promoviendo su función inmunosupresora.
- Este mecanismo de ubiquitinación es crítico para la supresión de células T mediada por LAG3 y representa un objetivo para la inmunoterapia del cáncer.
- La coexpresión de LAG3/CBL puede servir como un biomarcador predictivo para la respuesta a las terapias de bloqueo de LAG3.
Videos de Conceptos Relacionados
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...
02:33Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...