CARD9 Is a Novel Caspase Recruitment Domain-containing Protein That Interacts With BCL10/CLAP and Activates NF-κB

Abstract

BCL10/CLAP is an activator of apoptosis and NF؊B 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-B 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-B activator. To identify upstream signaling partners of BCL10, we performed a mammalian twohybrid analysis and identified CARD9 as a novel CARDcontaining protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-B. 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-B signaling.

The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens

“…1a). We also found no expression of Card9 in nonlymphoid organs such as brain, kidney and liver, consistent with previous findings 22 . Finally, we found high expression of Card9 in the mouse macrophage cell line RAW264.7 (Fig.…”

“…CARD9 has been suggested as a key adaptor in innate immune signaling by dectin-1-dependent NF-kB activation after fungal infection 24 . Although studies have shown that overexpression of CARD9 in HEK293 cells can activate NF-kB 22 , that NF-kB induction is very modest relative to the induction of other molecules involved in NF-kB activation, such as Bcl-10 and CARMA1 (ref. 25).…”

“…CARD9 is an adaptor molecule containing an N-terminal caspaserecruitment domain (CARD) and a C-terminal coiled-coil domain 22 . Studies have shown that CARD9 expression is found mainly in lymphoid tissues and correlates with gastrointestinal lymphoid malignancy 23 , providing additional clues to the potential involvement of CARD9 in inflammation and immune activation.…”

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

“…It was identified through a database search for CARD-containing proteins and shown to interact with Bcl10 [148]. Its expression seems to be restricted to myeloid cells, mainly macrophages, dendritic cells and neutrophils [148][149][150].…”

Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells

“…12,13) and the membrane-associated guanylate kinase family members CARD9 (ref. 14), CARD10 (ref. 15; also known as Bimp1; ref.…”