Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation.
Proteins containing a caspase recruitment domain (CARD) play pivotal roles in signal transduction leading to apoptosis and NF-kappaB activation and inflammation. Here we identify and characterize human and mouse CARD protein 6 (CARD6), CARD-containing proteins of unique structure. CARD6 associates with microtubules and interacts with receptor-interacting protein (RIP)-like interacting caspase-like apoptosis regulatory protein kinase (RICK), a CARD-containing member of the RIP family of protein kinases. These kinases are involved in multiple NF-kappaB signaling pathways important for innate and adaptive immune responses. Surprisingly, the CARDs of CARD6 and RICK were not required for their interaction; instead, mutational analysis revealed that the CARD of CARD6 negatively controls the association of these molecules. CARD6 also binds to RIP1, a RIP kinase homologue that lacks a CARD but contains a C-terminal death domain. Coexpression of RICK targets CARD6 to aggresomes via a mechanism that requires the CARD of RICK. Importantly, CARD6 expression has a synergistic effect on NF-kappaB activation induced by several independent signal transduction pathways. In summary, our results indicate that CARD6 is a regulator of NF-kappaB activation that modulates the functions of RIP kinase family members.
Dufner
Almut
A
Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada M5G 2C1.
Pownall
Scott
S
Mak
Tak W
TW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D053468:CARD Signaling Adaptor Proteins; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism
C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C478017:CARD6 protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse