HuR-HuB autoregulatory network governs inflammatory factors expression.

Short-lived mRNAs harbor AU-rich elements (AREs) in their 3' untranslated regions (3'UTRs) that are tightly regulated by ARE-binding proteins. While the Hu family stabilizes target mRNAs, our understanding is largely confined to HuR due to its ubiquitous expression. Other Hu members, long considered neuron-specific, remain incompletely characterized in non-neuronal cells. Notably, HuB is markedly upregulated in various tumors and under cellular stress, but the molecular mechanisms and functional significance underlying its upregulation remain elusive. Here, we show that inflammatory stimulation induces cytoplasmic translocation of HuR. HuR binds directly to the 3'UTR of HuB mRNA, thereby enhancing HuB mRNA stability. Upregulated HuB binds to the HuR nucleocytoplasmic shuttling sequence (HNS) through its RNA recognition motif 3 (RRM3) domain, thereby retaining HuR in the cytoplasm. Collectively, HuB and HuR form a heteromeric complex that coordinately regulates the stability of inflammatory factor mRNAs. Our study identifies HuB as a key post-transcriptional regulator of inflammatory genes and highlights the critical role of the HuB-HuR regulatory network in modulating the stability of inflammation-related mRNAs.