TANK

TANK Full Name

TRAF family member-associated NFKB activator

TANK Introduction

TANK, or I-TRAF (for TNF Receptor-Associated Factor), is an adaptor protein important for signal transduction. TANK was first identified as an interactor of TRAF2 and was demonstrated to function in conjunction with other TRAF family members to regulate the activation of NF-κB. TANK has a modular structure with several distinct functional domains, which allows it to function as a scaffold to recruit and assemble other important proteins in signaling complexes. In its early discovery phase, TANK was demonstrated to function as an activator through its overexpression causing enhancement of TRAF2-mediated activation of the NF-κB signaling pathway. The complexity of TANK functions has since been revealed, as further studies showed that TANK can act in very different ways, even opposite, as an activator or an inhibitor depending on the signaling pathway and cell context.

The functions of TANK extend far beyond regulating the canonical NF-κB pathway; it plays a vital role in antiviral innate immune responses. Here, TANK serves as a central adapter protein that links the upstream TRAF proteins (mainly TRAF3) to the downstream TBK1-IKKε kinase complex. Via this connection, TANK mediates phosphorylation and activation of the transcription factors IRF3 and IRF7 by TBK1 and IKKε, and is thus an important intermediate step in inducing the expression of Type I IFN to establish an antiviral state. Furthermore, TANK's regulatory role in the NF-κB pathway also exhibits duality. On one hand, it can positively regulate NF-κB activation via interactions between its N-terminal domain and IKKε/TBK1. Conversely, it can also have positive regulatory effects on NF-κB activation through the N-terminal domain interactions with IKKε/TBK1. SARM can also negatively regulate NF-κB signalling, which could be a consequence of the recruitment of deubiquitinating enzymes or due to the C-terminal domain of SARM, finely tuning the magnitude and kinetics of the inflammatory response.

Figure 1. A model illustrating the TANK/MCPIP1/USP10-mediated negative feedback response to suppress NF-B activation via deubiquitinating TRAF6 and NEMO. (Source: Wang W, et al. 2015)

TANK-deficient mice develop spontaneous autoimmune diseases resembling SLE, including autoimmune glomerulonephritis. Production of high titer anti-double stranded DNA (anti-dsDNA) antibodies and antinuclear antibodies (ANA), serological markers used for lupus diagnosis, is also seen in TANK-deficient mice. This supports the notion that TANK is required for the induction of tolerance and regulation of autoimmune responses under physiological conditions. In cancer biology, on the other hand, dysregulated TANK expression has been shown to be associated with the development and progression of several cancers. For example, in Glioblastoma, TANK was shown to be significantly upregulated, where its expression positively correlated with the malignancy of the tumor and patient survival. In these tumors, TANK overexpression was proposed to promote tumor progression by contributing to the activation of pro-survival signaling pathways such as ERK1/2 and AKT. Dysregulated TANK expression or involvement in other cancers including cervical cancer and osteosarcoma have also been described.

Alternate Names for TANK

TANK; TRAF family member-associated NFKB activator; ITRAF; TRAF2; I-TRAF; TRAF family member-associated NF-kappa-B activator; TRAF-interacting protein

• 1. Wang W, et al. TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase. J Biol Chem. 2015 May 22;290(21):13372-85.
  2. Kawagoe T, et al. TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol. 2009 Sep;10(9):965-72.