Nuclear Envelope Lamin-A Couples Actin Dynamics with Immunological Synapse Architecture and T Cell Activation

被引:68
|
作者
Gonzalez-Granado, Jose M. [1 ]
Silvestre-Roig, Carlos [1 ]
Rocha-Perugini, Vera [3 ]
Trigueros-Motos, Laia [1 ]
Cibrian, Danay [2 ,3 ]
Morlino, Giulia [2 ]
Blanco-Berrocal, Marta [1 ]
Osorio, Fernando G. [4 ]
Freije, Jose M. P. [4 ]
Lopez-Otin, Carlos [4 ]
Sanchez-Madrid, Francisco [2 ,3 ]
Andres, Vicente [1 ]
机构
[1] CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
[2] CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
[3] Inst Invest Sanitaria Princesa, Serv Inmunol, Hosp Princesa, Inst Invest, Madrid 28006, Spain
[4] Univ Oviedo IUOP, Dept Bioquim & Biol Mol, Oviedo 33006, Spain
关键词
ACUTE LYMPHOBLASTIC-LEUKEMIA; LYMPH-NODES; RETROGRADE FLOW; DENDRITIC CELLS; HUMAN TISSUES; F-ACTIN; PROTEIN; CYTOSKELETON; EXPRESSION; RECEPTOR;
D O I
10.1126/scisignal.2004872
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 naive 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.
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页数:13
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