Dataset Information

Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation.

ABSTRACT: 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.

SUBMITTER: Dufner A

PROVIDER: S-EPMC1327733 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Orf virus (ORFV) is a highly epitheliotropic parapoxvirus with zoonotic significance that induces proliferative lesions in the skin of sheep, goats, and humans. Several viral proteins carried by ORFV, including nuclear factor-κB (NF-κB) inhibitors, play important roles in hijacking host-associated proteins for viral evasion of the host innate immune response. However, the roles of proteins with unknown functions in viral replication and latent infection remain to be explored. Here, we present data demonstrating that the ORF120, an early-late ORFV-encoded protein, activates the NF-κB pathway in the early phase of infection, which implies that ORFV may regulate NF-κB through a biphasic mechanism. A DUAL membrane yeast two-hybrid system and coimmunoprecipitation experiments revealed that the ORF120 protein interacts with Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1). The overexpression of the ORF120 protein can efficiently increase the expression of G3BP1 and nuclear translocation of NF-κB-p65 in primary ovine fetal turbinate (OFTu) and HeLa cells. The knockdown of G3BP1 significantly decreased ORF120-induced NF-κB activation, indicating that G3BP1 is involved in ORF120-induced NF-κB pathway activation. A dual-luciferase reporter assay revealed that ORF120 could positively regulate the NF-κB pathway through the full-length G3BP1 or the domain of G3BP1RRM+RGG. In conclusion, we demonstrate, for the first time, that the ORF120 protein is capable of positively regulating NF-κB signaling by interacting with G3BP1, providing new insights into ORFV pathogenesis and a theoretical basis for antiviral drug design. IMPORTANCE As part of the host innate response, the nuclear factor-κB (NF-κB) pathway plays a partial antiviral role in nature by regulating the innate immune response. Thus, the NF-κB pathway is probably the most frequently targeted intracellular pathway for subversion by anti-immune modulators that are carried by a wide range of pathogens. Various viruses, including poxviruses, carry several proteins that prepare the host cell for viral replication by inhibiting cytoplasmic events, leading to the initiation of NF-κB transcriptional activity. However, NF-κB activity is hypothesized to facilitate viral replication to a great extent. The significance of our research is in the exploration of the activation mechanism of NF-κB induced by the Orf virus (ORFV) ORF120 protein interacting with G3BP1, which helps not only to explain the ability of ORFV to modulate the immune response through the positive regulation of NF-κB but also to show the mechanism by which the virus evades the host innate immune response.

Dataset Information

Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets