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CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa
1Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. bertin@mpi.com
Insights
Researchers identified CARD9 as a novel upstream activator of BCL10 (B-cell lymphoma 10) and NF-kappaB signaling. This discovery sheds light on the molecular mechanisms underlying B-cell lymphomas and apoptosis regulation.
Area of Science:
- Molecular Biology
- Cell Signaling
- Immunology
Background:
- BCL10 (B-cell lymphoma 10) is a key regulator of apoptosis and NF-kappaB signaling pathways.
- Dysregulation of BCL10 is implicated in mucosa-associated lymphoid tissue B-cell lymphomas.
- The N-terminal caspase recruitment domain (CARD) of BCL10 is crucial for its function in protein interactions.
Purpose of the Study:
- To identify novel upstream signaling partners of BCL10.
- To elucidate the role of CARD9 in BCL10-mediated signaling.
- To understand the molecular basis of NF-kappaB activation by BCL10.
Main Methods:
- Mammalian two-hybrid analysis to identify BCL10 interacting proteins.
- Co-immunoprecipitation to confirm protein-protein interactions.
- Reporter assays to assess NF-kappaB activation.
Main Results:
- CARD9 was identified as a novel CARD-containing protein interacting with BCL10's CARD domain.
- CARD9 binds to BCL10 and activates NF-kappaB signaling when expressed in cells.
- Endogenous CARD9 and BCL10 form a pre-existing signaling complex.
- CARD9 self-associates and possesses coiled-coil motifs, suggesting oligomerization.
Conclusions:
- CARD9 acts as an upstream activator of BCL10.
- CARD9 is a novel component in the NF-kappaB signaling pathway.
- The BCL10-CARD9 complex plays a significant role in cellular signaling.
Abstract:
BCL10/CLAP is an activator of apoptosis and NF-kappaB signaling pathways and has been implicated in B cell lymphomas of mucosa-associated lymphoid tissue. Although its role in apoptosis remains to be determined, BCL10 likely activates NF-kappaB through the IKK complex in response to upstream stimuli. The N-terminal caspase recruitment domain (CARD) of BCL10 has been proposed to function as an activation domain that mediates homophilic interactions with an upstream CARD-containing NF-kappaB activator. To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB. Furthermore, endogenous CARD9 is found associated with BCL10 suggesting that both proteins form a pre-existing signaling complex within cells. CARD9 also self-associates and contains extensive coiled-coil motifs that may function as oligomerization domains. We propose here that CARD9 is an upstream activator of BCL10 and NF-kappaB signaling.