Rabbit Anti-Human DTX4 (a.a. 501-600) Polyclonal antibody

Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5'ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3(-/-) primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells. RNA viruses can be detected by immune cell pattern recognition receptors, such as RLRs, resulting in MAVS-TBK1-IRF3 signalling and production of antiviral type 1 interferons. Here the authors show that macrophage TRAF3-interacting protein 3 regulates this signalling pathway by interacting with TRAF3 and TBK1 to suppress interferon responses.

Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma, and along with pomalidomide are being investigated in a variety of other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about the primary mode of therapeutic action in patients with cancer. This paper describes a microarray study of the in vitro and in vivo effects of these drugs, and contrasts the difference in gene profiles achieved in the two models. In the current study, Agilent whole mouse genome oligonucleotide microarrays (44 K) were used to examine alterations in gene expression of colorectal cancer cells after treatment. Venn analysis revealed a divergence of gene signature for pomalidomide and lenalidomide, which although similar in vitro, different in vivo. Several clusters of genes involved in various cellular processes such as immune response, cell signalling and cell adhesion were altered by treatment, and common to the three drugs. Notably, the expressions of linked genes within the Notch/Wnt signalling pathway, including kremen2 and dtx4, highlighted a possible novel mechanistic pathway for these drugs. This study also showed that gene signatures were not greatly divergent in the models, and recapitulated the complex nature of these drugs. Overall, these microarray studies highlighted the diversity of this class of drug, which have effects ranging from cell signalling to translation initiation.