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A novel gene coding for a Fas apoptosis inhibitory molecule (FAIM) isolated from inducibly Fas-resistant B
T J Schneider1, G M Fischer, T J Donohoe
1Department of Microbiology, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Abstract:
The sensitivity of primary splenic B cells to Fas-mediated apoptosis is modulated in a receptor-specific fashion. Here we used a differential display strategy to detect cDNAs present in B cells rendered Fas resistant but absent in those rendered Fas sensitive. This led to the cloning and characterization of a novel 1.2-kb gene that encodes a Fas apoptosis inhibitory molecule (FAIM). faim-transfected BAL-17 B lymphoma cells were less sensitive by half or more to Fas-mediated apoptosis than were vector-transfected controls, using Fas ligand-bearing T cells or a cytotoxic anti-Fas antibody to trigger Fas, and this was associated with inhibition of Fas- induced poly-ADP ribose polymerase (PARP) cleavage. In primary B cells, the time course of faim mRNA and FAIM protein expression correlated with the induction of Fas resistance by surface (s)Ig engagement. Thus, FAIM is an inducible effector molecule that mediates Fas resistance produced by sIg engagement in B cells. However, faim is broadly expressed in various tissues and the faim sequence is highly conserved evolutionarily, suggesting that its role extends beyond lymphocyte homeostasis. As FAIM has no significant regions of homology to other gene products that modulate Fas killing, it appears to represent a distinct, new class of antiapoptotic protein.
Insights
Researchers discovered a new protein, Fas apoptosis inhibitory molecule (FAIM), that protects B cells from programmed cell death. This molecule is induced by surface immunoglobulin engagement and represents a novel class of antiapoptotic proteins.
Area of Science:
- Immunology
- Molecular Biology
- Cell Death Research
Background:
- B cells possess sensitivity to Fas-mediated apoptosis, crucial for immune regulation.
- This sensitivity can be modulated, indicating the involvement of specific regulatory molecules.
Purpose of the Study:
- To identify novel genes involved in regulating Fas-mediated apoptosis in B cells.
- To characterize the function and expression of a newly discovered apoptosis inhibitory molecule.
Main Methods:
- Differential display screening to identify differentially expressed cDNAs.
- Gene transfection in B lymphoma cells (BAL-17) to assess functional impact.
- Analysis of Fas-mediated apoptosis induction and poly-ADP ribose polymerase (PARP) cleavage.
- Correlation of gene and protein expression with surface immunoglobulin (sIg) engagement in primary B cells.
Main Results:
- A novel 1.2-kb gene encoding Fas apoptosis inhibitory molecule (FAIM) was identified.
- FAIM-transfected cells exhibited significantly reduced sensitivity to Fas-mediated apoptosis.
- FAIM expression was induced by sIg engagement in primary B cells, correlating with Fas resistance.
- FAIM inhibits Fas-induced PARP cleavage, a key event in apoptosis.
Conclusions:
- FAIM is an inducible effector molecule mediating Fas resistance in B cells upon sIg engagement.
- FAIM represents a distinct class of antiapoptotic proteins with potential roles beyond lymphocyte homeostasis.
- The broad expression and evolutionary conservation of FAIM suggest a fundamental role in cellular protection.