Nuclear envelope lamin-A couples actin dynamics with immunological synapse architecture and T cell activation.
In many cell types, nuclear A-type lamins regulate multiple cellular functions, including higher-order genome organization, DNA replication and repair, gene transcription, and signal transduction; however, their role in specialized immune cells remains largely unexplored. We showed that the abundance of A-type lamins was almost negligible in resting naïve T lymphocytes, but was increased upon activation of the T cell receptor (TCR). The increase in lamin-A was an early event that accelerated formation of the immunological synapse between T cells and antigen-presenting cells. Polymerization of F-actin in T cells is a critical step for immunological synapse formation, and lamin-A interacted with the linker of nucleoskeleton and cytoskeleton (LINC) complex to promote F-actin polymerization. We also showed that lamin-A expression accelerated TCR clustering and led to enhanced downstream signaling, including extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, as well as increased target gene expression. Pharmacological inhibition of the ERK pathway reduced lamin-A-dependent T cell activation. Moreover, mice lacking lamin-A in immune cells exhibited impaired T cell responses in vivo. These findings underscore the importance of A-type lamins for TCR activation and identify lamin-A as a previously unappreciated regulator of the immune response.
Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
José María
JM
González-Granado
Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Carlos
C
Silvestre-Roig
Vascular Biology and Inflammation. CNIC, Madrid, Spain.|Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
Vera
V
Rocha-Perugini
Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Laia
L
Trigueros-Motos
Vascular Biology and Inflammation. CNIC, Madrid, Spain.|Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
Danay
D
Cibrián
Vascular Biology and Inflammation. CNIC, Madrid, Spain.|Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
Giulia
G
Morlino
Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Marta
M
Blanco-Berrocal
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo-IUOPA, Oviedo, Spain.
Fernando Garcia
FG
Osorio
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo-IUOPA, Oviedo, Spain.
José María Pérez
JMP
Freije
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo-IUOPA, Oviedo, Spain.
Carlos
C
López-Otín
Vascular Biology and Inflammation. CNIC, Madrid, Spain.|Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
Francisco
F
Sánchez-Madrid
Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Vicente
V
Andrés
D008841:Actin Cytoskeleton / Q000235:genetics / Q000276:immunology*; D000199:Actins / Q000235:genetics / Q000276:immunology*; D000818:Animals; D006801:Humans; D054992:Immunological Synapses / Q000235:genetics / Q000276:immunology*; D019169:Jurkat Cells; D034904:Lamin Type A / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D000199:Actins; C494847:LMNA protein, human; D034904:Lamin Type A; D011948:Receptors, Antigen, T-Cell; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3