5pppRNA

5pppRNA refers to RNA molecules that possess a 5′ triphosphate group, often written as 5′-pppRNA. In vertebrate innate immunity, these molecules can act as pathogen-associated molecular patterns (PAMPs) that signal the presence of viral infection or other non-self RNA. Cellular RNAs are typically capped or processed to remove exposed 5′ triphosphates, reducing recognition as 5′pppRNA.

Recognition and signaling are primarily mediated by the RIG-I receptor. RIG-I detects RNA bearing a 5′ triphosphate and, when accompanied by short double-stranded regions, undergoes a conformational change that enables interaction with the MAVS adaptor on mitochondria. This triggers downstream signaling that activates transcription factors such as IRF3, IRF7, and NF-κB, leading to the production of type I interferons and pro-inflammatory cytokines. MDA5, another RIG-I-like receptor, responds preferentially to long double-stranded RNAs, illustrating a division of labor among cytosolic RNA sensors.

Natural and synthetic sources. In nature, 5′pppRNAs arise from replication intermediates of many RNA viruses and, in some contexts, from transcription by RNA polymerase III. Cellular processes generally remove the 5′ triphosphate to avoid detection. Synthetic 5′pppRNAs can be produced by in vitro transcription and are used to study RIG-I signaling or as immunostimulatory agents.

Applications and research. 5′pppRNA serves as a tool to investigate innate immune pathways, and has been explored for antiviral and cancer immunotherapy strategies. Delivery approaches aim to enable cytosolic access while minimizing off-target effects, highlighting ongoing research into the therapeutic potential and safety of 5′pppRNA-based approaches.