Abstract Patients with autoimmune diseases, such as systemic lupus erythematosus (SLE), often have skewed B cell population ratios, accumulation of autoantibodies, and an increased amount proinflammatory cytokines aiding in disease development. Genome-wide association studies (GWAS) strongly linked polymorphisms A20, encoded by TNFAIP3, to diseases including SLE. A20 functions inhibit the activ...

Symbol Values Units Description Comments W0 2 10 12 l cell volume Assumed [1] kv = V=U 5 cytoplasmic to nuclear volume Assumed kb 4 10 6 s 1ml=ng receptor activation rate Assumed kf 6 10 4 s 1 receptor inactivation rate Fitted [3] q1 1:5 10 7 s 1 NFB driven activation of I B and A20 genes Fitted q2 10 6 s 1 I B mediated NFB dissociation from I B and A20 sites Assumed KN 104 total number of IKKK...

Many B cell cancers are characterized in part by the dysregulation of the NF-kappaB signaling pathway. A new study identifies somatic mutations in TNFAIP3, the gene encoding the NF-kappaB inhibitor A20, in Hodgkin lymphomas and primary mediastinal lymphomas. These data reveal the role of A20 as a tumor suppressor protein.

NF-κB is a key transcription factor that regulates innate immune response. Its activity is tightly controlled by numerous feedback loops, including two negative loops mediated by NF-κB inducible inhibitors, IκBα and A20, which assure oscillatory responses, and by positive feedback loops arising due to the paracrine and autocrine regulation via TNFα, IL-1 and other cytokines. We study the NF-κB ...

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral inter...

The IL-17/IL-17R axis has controversial roles in cancer, which may be explained by tumor-specific results. Here, we describe a novel molecular mechanism underlying IL-17RC-controlled tumor-specific proliferation. Triggered by IL-17RC knockdown (KD), B16 melanoma and 4T1 carcinoma cells inversely altered homeostatic tumor proliferation and tumor growth in vitro and in vivo. In contrast to the ex...

Linear polyubiquitination of proteins has recently been implicated in NF-κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced ...

LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-κB pathway through linear polyubiquitination of NEMO (NF-κB essential modulator, also known as IKKγ) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-κB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via the C-terminal seventh ...

The nuclear factor B (NFB) plays a central role in the regulation of genes implicated in immune responses, inflammatory processes, and apoptotic cell death. The zinc finger protein A20 is a cellular inhibitor of NFB activation by various stimuli and plays a critical role in terminating NFB responses. The underlying mechanism for NFB inhibition by A20 is still unknown. A20 has been shown to inte...

Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of ap...