In the cell’s nuclear control room, RNA-binding proteins (RBPs) are the DJs of gene expression. In a new study, Deshaies et al. (1) explore two isoforms of hnRNP A1 (A1 and A1B members of the hnRNP family) involved in RNA splicing, transport, and metabolism. While both isoforms are structurally similar and co-expressed across tissues, they have distinct impacts on gene regulation, with over 300 genes differentially expressed between them.
Among the most striking differences, hnRNP A1, but not A1B, emerges as a key suppressor of the innate immune response under homeostatic conditions. Under basal conditions, hnRNP A1 lowers the volume on interferon-stimulated genes (ISGs), including double-stranded RNA sensors like the OAS family, which activate RNase L, a key antiviral effector, helping to prevent an unnecessary “antiviral party.” This keeps the immune system on standby, avoiding unnecessary activation. But when hnRNP A1 is depleted, the brakes come off: PKR is activated, RNase L bodies (RLBs) form more quickly and abundantly, and type I interferons (IFNA2, IFNB1) are strongly induced. Interestingly, overexpressing A1B does not replicate these effects, pointing to a specific role for A1 in immune regulation.
During dsRNA stress, hnRNP A1 also translocates from the nucleus to the cytoplasm, partially co-localizing with G3BP1-positive RLBs, hinting at a direct role in cytoplasmic stress responses. These findings establish hnRNP A1 as a critical tuner of antiviral defense: restraining immune activity under normal conditions, but stepping back when it’s time to respond. As such, its dysregulation could have important consequences in contexts like viral infection, neuroinflammation, or autoimmune disease.
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