1. Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling
Xiaoxia Li Cytokine. 2008 Feb;41(2):105-13. doi: 10.1016/j.cyto.2007.09.015. Epub 2007 Dec 3.
Coordinated regulation of T and B cell-mediated immune responses plays a critical role in the control and modulation of autoimmune diseases. This review is focused on the adapter molecule Act1 and its regulation of autoimmunity through its impact on both T and B cell-mediated immune responses. Whereas Act1 molecule is an important negative regulator for B cell-mediated humoral immune responses through its function in CD40L and BAFF signaling, recent studies have shown that Act1 is also a key positive signaling component for IL-17 signaling pathway, critical for T(H)17-mediated autoimmune and inflammatory responses. The dual functions of Act1 are evident in Act1-deficient mice that displayed B cell-mediated autoimmune phenotypes (including dramatic increase in peripheral B cells, lymphadenopathy and splenomegaly, hypergammaglobulinemia and Sjogren's disease in association with Lupus Nephritis), but showed resistance to T(H)17-dependent EAE and colitis. Such seemingly opposite functions of Act1 in CD40-BAFFR and IL-17R signaling are orchestrated by different domains in Act1. Whereas Act1 interacts with the IL-17R through the C-terminal SEFIR domain, Act1 is recruited to CD40 and BAFFR indirectly, which is mediated by TRAF3 through the TRAF binding site in Act1. Such delicate regulatory mechanisms may provide a common vehicle to promote balance between host defense to pathogens and tolerance to self.
2. Act1: A Psoriasis Susceptibility Gene Playing its Part in Keratinocytes
Ryan P Hobbs, Susan H Smith, Spiro Getsios J Invest Dermatol. 2017 Jul;137(7):1410-1412. doi: 10.1016/j.jid.2017.01.023. Epub 2017 Apr 5.
Unchecked inflammation, impaired keratinocyte differentiation, and heightened host defense responses typify psoriasis. Lambert et al. make clever use of psoriasis patient genetics and whole transcriptome RNA-Seq analysis to implicate Act1 in these seemingly variegated processes by keeping IL-17 receptor signaling in check while supporting differentiation and limiting innate immune responses in human keratinocytes.
3. IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP-AREG Axis
Zengyang Yu, Qian Yu, Hui Xu, Xing Dai, Yingyuan Yu, Lian Cui, Youdong Chen, Jun Gu, Xilin Zhang, Chunyuan Guo, Yuling Shi J Invest Dermatol. 2022 Sep;142(9):2343-2352. doi: 10.1016/j.jid.2022.02.016. Epub 2022 Mar 15.
Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo-YAP signaling pathway plays a vital role in cell survival and tissue growth, and its target gene, AREG, has been reported to promote the development of psoriasis. However, whether IL-17A promotes keratinocyte proliferation through regulating Hippo-YAP signaling has not been explored. In this study, we show that the YAP-AREG pathway is activated in human psoriatic skin and is suppressed by IL-17A antagonist secukinumab and that imiquimod and IL-17A administration activates the YAP-AREG axis in mice epidermis. In vitro studies using HaCaT and normal human epidermal keratinocyte cells suggest that IL-17A enhances AREG expression and keratinocyte proliferation by activating Hippo-YAP signaling. Mechanistically, IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1-LATS1 interaction and YAP dephosphorylation. Together, our findings reveal a previously unknown mechanism in which IL-17A promotes keratinocyte proliferation in psoriasis, namely through activating YAP-AREG signaling.
