CD3ε recruits Numb to promote TCR degradation.
Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3ε that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3ε chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.
Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, 18100 Granada, Spain Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
Nadia
N
Martin-Blanco
Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, 18100 Granada, Spain.
Daniel
D
Jiménez Teja
Departamento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-SODERCAN, Santander, Spain.
Gabriel
G
Bretones
Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
Aldo
A
Borroto
Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, 18100 Granada, Spain.
Michael
M
Caraballo
Laboratory of Molecular Pathology, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy.
Isabella
I
Screpanti
Departamento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-SODERCAN, Santander, Spain.
Javier
J
León
Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain.
Balbino
B
Alarcón
Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, 18100 Granada, Spain mcanelles@ipb.csic.es.
Matilde
M
Canelles
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C485468:Cd3e protein, mouse; D008565:Membrane Proteins; C078332:Nck protein; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D015513:Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse
T-cell activation; T-cell differentiation; T-cell receptor; lymphocyte signaling