HuR coordinates cytokine translation and maturation through ER-associated RNA granules

Efficient biosynthesis and secretion of inflammatory mediators is indispensable for robust immune responses. This process relies on the coordination of mRNA translation and protein processing in the endoplasmic reticulum (ER). RNA-binding proteins (RBPs) govern the spatial organization of mRNA translation, yet how RBPs modulate inflammatory factor production and maturation remains poorly defined. Here, we uncover a regulatory role of the RBP HuR in inflammatory-factor mRNA translation. We find that HuR physically interacts with the ER chaperone calnexin (CANX), bringing together inflammatory factor mRNAs, the calnexin quality control complex, and the translocon in discrete ER subdomains. Mechanistically, HuR undergoes phase separation and assembles membraneless RNA granules, which are selectively enriched in inflammatory mRNAs. This allows juxtaposed calnexin to rapidly recognize their corresponding nascent polypeptides. Collectively, our findings provide molecular evidence that RBPs spatially coordinate protein translation and processing via phase separation, offering new insights into regulatory mechanisms underlying efficient inflammatory-mediator production.