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LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing
G R Screaton1, X N Xu, A L Olsen
1Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Abstract:
Fas and TNF-R1 are cysteine-rich cell surface receptors related to the low-affinity nerve growth factor receptor family. Engagement of these receptors by their respective ligands, FasL and tumor necrosis factor, leads to apoptosis that is signaled through a conserved intracellular portion of the receptor termed the "death domain." We have cloned a new member of this family, lymphocyte-associated receptor of death (LARD), which leads to spontaneous apoptosis when expressed in 293T cells. The expression of LARD is more tightly regulated than that of either Fas or TNF-R1 as it is found predominantly on lymphocytes (T and B cells) but not on macrophages or a number of transformed lymphocyte cell lines. Alternative pre-mRNA splicing generates at least 11 distinct isoforms of LARD. The full-length isoform, LARD-1, extends to include the transmembrane and death domains, whereas the other isoforms encode potentially secreted molecules. Naive B and T cells express very little LARD-1 but express combinations of the other isoforms. Upon T cell activation, a programmed change in alternative splicing occurs so that the full-length, membrane-bound LARD-1 predominates. This may have implications for the control of lymphocyte proliferation following activation.
Insights
A new receptor, lymphocyte-associated receptor of death (LARD), triggers apoptosis in lymphocytes. Its expression and splicing change upon T cell activation, potentially regulating lymphocyte proliferation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Fas and TNF-R1 are cell surface receptors mediating apoptosis via their death domains.
- These receptors belong to the nerve growth factor receptor family.
Purpose of the Study:
- To clone and characterize a novel member of the Fas/TNF-R1 receptor family.
- To investigate the expression pattern and alternative splicing of this new receptor, termed LARD.
- To explore the role of LARD in lymphocyte apoptosis and proliferation.
Main Methods:
- Cloning of the LARD gene.
- Expression studies in 293T cells.
- Analysis of LARD alternative splicing and isoform expression in lymphocytes.
- Investigation of LARD expression in naive versus activated T cells.
Main Results:
- A new receptor, lymphocyte-associated receptor of death (LARD), was identified.
- LARD expression is predominantly found in lymphocytes (T and B cells).
- Alternative splicing of LARD generates at least 11 isoforms, including a full-length membrane-bound form (LARD-1).
- Naive lymphocytes express low levels of LARD-1 but various other isoforms.
- T cell activation induces a shift towards predominant expression of the full-length LARD-1 isoform.
Conclusions:
- LARD is a novel death domain-containing receptor expressed in lymphocytes.
- Alternative splicing of LARD is tightly regulated and changes upon T cell activation.
- The programmed shift in LARD splicing may play a critical role in controlling lymphocyte proliferation post-activation.