The role of Act1 in NF-кB activation

2018-09-21

Introduction 

NF-кB activator 1, named Act1, is a 60-kDa (574-aa) polypeptide. Based on its interaction with IKKγ, Act1can be cloned by Leonardi et al. through a yeast-two hybrid screening. Instead of enzymatic domain, Act1 contains a coiled-coil at the C terminus and helix-loop-helix at the N terminus. That is to say, Act1 does not have any enzymatic domain. In addition, Act1 contains two TRAF binding sites, such as EERPA (residues 333-337) and EEESE (residues 38-42). The data show that Act1 activates the NF-кB through the TAK1 and IKK signaling cascade. Some overexpressed signaling components in the IL-1, TNFα, and related pathways often activate NF-кB, constitutively. Therefore, Act1 is likely to participate in pathway involving NF-кB activation.

Pharmacologic action

Act1 does not have any enzymatic domain, but it contains a helix-loop-helix domain in its N-terminal portion and a coiled-coil structure at the C terminus. So, it is likely that it functions as a structural component through protein-protein interactions. Some data indicate that Act1 probably activate NF-кB through IkB kinase (IKK) and it activates IKK through its helix-loop-helix domain. What's more, the activation of NF-кB by Act1 seems to be through the NIK-IKK complex, because a NIK dominant negative mutant protein inhibited Act1-induced NF-кB activation. Meanwhile, Act1 associates with and activates IKK, resulting in the release of NF-кB from its complex with IkB. Of course, many signaling pathways that lead to NF-кB activation also activate activator protein 1 (AP-1) and activating transcription factor (ATF) through Jun kinase (JNK). Interestingly, Act1 can activate both NF-кB and JNK, suggesting that it might be part of a multifunctional complex involved in the activation of both NF-кB and JNK, that is to say, it lies upstream of the branch point that separates these two pathways.

Function

In fact, Act1-mediated NF-кB activation is regulated by TRAF3 that is one of the Act1-interacting proteins. Importantly, previous studies showed that TRAF3 plays an important role in LTβ-mediated apoptosis and the ligation of CD40 can lead to apoptosis in some epithelial cells. On one hand, both endogenous Act1 and TRAF3 are recruited to the CD40 receptor after stimulation with CD40L in epithelial cells, and on the other hand, they also interact with each other, which strongly suggests that the expression levels of Act1 and TRAF3 are likely to play key roles in distinguishing whether leads to apoptosis or CD40L activates NF-кB. Interestingly, expression of Act1 protects Act1-Null C33A cells from CD40-mediated apoptosis.

Pharmacokinetics and metabolism

Previous studies showed that Act1 is expressed highly in placenta, thymus and kidney; moderately in skeletal muscle, heart, lung, colon, liver and small intestine; and expressed at a very low level in spleen, peripheral blood leukocytes and brain. Act1 is a polypeptide, which can be quickly metabolize and cleared from the systemic circulation.

References:

Soren Ulrik Sonder, Sun Saret, Wanhu Tang, Dan E. Sturdevant, Stephen F. Porcella, IL-17-induced NF-кB Activation via CIKS/Act1. Journal of Biological Chemistry, 2011, 268(15), 12881-12890.

Xiaoxia Li, Mairead Commane, Huiqin Nie, Act1, an NF-кB-activating protein. PNAS, 2000, 97(19), 10489-10493.

Qian, Y., Zhao, Z., Jiang, Z., & Li, X. (2002). Role of NFκB activator Act1 in CD40-mediated signaling in epithelial cells. Proceedings of the National Academy of Sciences, 99(14), 9386-9391.

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