A NIK–SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB

Abstract

SUMMARY The non-canonical NF-κB signaling cascade is essential for lymphoid organogenesis, B-cell maturation, osteoclast differentiation, and inflammation in mammals1,2, whereas dysfunction of this system is associated with human diseases, including immunological disorders and cancer3–6. While controlled expression of NF-κB Inducing Kinase (NIK) is the rate-limiting step in non-canonical NF-κB activation2,7, mechanisms of inhibition remain largely unknown. Here, we report the identification of the sine oculis homeobox homolog family transcription factors SIX1 and SIX2 as essential inhibitory components of the non-canonical NF-κB signaling pathway. The developmentally silenced SIX-proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit RelA and RelB trans-activation function in a negative feedback circuit. In support of a physiologically pivotal role for SIX-proteins in host immunity, human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/p53-driven lung adenocarcinoma cells from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents, small-molecule activators of the non-canonical NF-κB pathway. Collectively, our study reveals a NIK-SIX signaling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.

The emerging role of miR‐128 in musculoskeletal diseases

“…Tiribuzi and Chen's research groups demonstrated that upregulation of miR‐128 was related to impaired beta‐amyloid (1‐42) degradation and decreased hippocampus‐related contextual learning in AD patients and mice (J. Chen et al, 2016; Tiribuzi et al, 2014). In contrast, knockout or disruption of miR‐128 suppressed the development of AD in mice by restoring synaptic function and rescuing impaired memory via targeting PPARγ and STIM2 (Deng et al, 2020; Y. Liu et al, 2019). In plasma samples of older patients with mild cognitive impairment, miR‐128 was also upregulated, in comparison to age‐matched controls (Sheinerman et al, 2013).…”

“…Of particular interest is miR‐128, which was reported to play an important role in cell proliferation, differentiation, and apoptosis (Huang et al, 2018; Z. Li et al, 2018; Xiao et al, 2018; Ye et al, 2018). Previous studies have demonstrated that miR‐128 is enriched in the brain (Tan et al, 2013; Wulczyn et al, 2007) and plays a pivotal role in nervous system diseases, including epilepsy (D. Z. Chen et al, 2019), depression (Roy et al, 2020) and Alzheimer's disease (Y. Liu et al, 2019). Furthermore, miR‐128 was implicated in the development of a variety of tumors, including lung cancer (J. Pan et al, 2018), breast cancer (Y. Li et al, 2019), glioma (Fu et al, 2018), pancreas cancer (Han et al, 2018), and thyroid carcinoma (Cao et al, 2019).…”

SMAC mimetic birinapant inhibits hepatocellular carcinoma growth by activating the cIAP1/TRAF3 signaling pathway

“…Immunohistochemical staining. immunohistochemical staining was performed as previously described (15). Subcutaneous tumor tissues (n=18) were fixed in 4% formalin at room temperature for 48 h and embedded in paraffin.…”

Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer

“…Specifically, in differentiated macrophages, cytokine stimulation or pathogen infection resulted in reactivation of developmentally silenced SIX proteins by NIK-mediated suppression of the ubiquitin proteosome pathway. The net result of SIX1/2 reactivation was attenuation of inflammatory gene expression in response to persistent activation of the noncanonical NF-κB signaling cascade [ 36 ]. Together, these studies demonstrate that NIK plays important roles in regulating innate, as well as adaptive, immunity through macrophage functions in the pathogenesis of human disease.…”