分子生物学国家重点实验室特邀报告 宋尔卫教授
A cytoplasmic NFκB interacting long noncoding RNA directly blocks IκB phosphorylation and suppresses breast cancer metastasis

Long noncoding RNAs (lncRNAs) of more than 200 bases are a large class of RNAs involved in many biological processes. Presently, only a small number of lncRNAs have been characterized functionally and are largely shown to modulate gene expression by decoying, guiding, or scaffolding other regulatory proteins that control epigenetic silencing, transcription, translation and stability of mRNA. The ability of lncRNAs to interact with specific proteins suggests that they may play a critical but yet unappreciated role in signal transduction. Here, we show that a cytoplasmic NF-KappaB Interacting LncRNA (NKILA), although upregulated by NFkB, is essential to prevent over-activation of NFkB pathway in both resting and inflammation-stimulated breast epithelia, suggesting that NKILA serves as a gatekeeper to restrain NFkB signaling even in physiological conditions. Moreover, in highly invasive cancer cells, NKILA is degraded by miR103/107, leading to aberrant NFkB activation, and reduced NKILA is associated with breast cancer metastasis and poor patient prognosis. Unlike other NFkB suppressors, NKILA is the first identified negative regulator that directly inhibits IKK-induced IkB phosphorylation without influencing IKK activities. NKILA function depends on its specific 5’ hairpin motif that mimics NFkB binding motif and binds to p65, and a discrete triple-hairpin loop motif that physically masks the phosphorylation site of IkB. These findings identify a new function of lncRNAs that regulate signal transduction by directly acting on functional domains of signaling proteins without mobilizing other regulatory molecules, thus uncovering a new layer of signal transduction checkpoint that suppresses cancer progression.