LMU researchers have decoded the intricate interaction of different enzymes around the innate immune receptor toll-like receptor 7 (TLR7), which is crucial in protecting our bodies from viruses. Toll-like receptor 7 (TLR7) is situated in the dendritic cells of our immune system and has a vital function in our natural defense against viruses. TLR7 specifically identifies single-stranded DNA and RNA molecules that are characteristic of viruses.The TLR7 receptor responds to viral and foreign RNA by triggering the release of inflammatory mediators. Dysfunctions in TLR7 are also involved in autoimmune diseases, highlighting the need to understand and potentially control its activation mechanism. Professor Veit Hornung and Marleen Bérouti, along with researchers from the Gene Center Munich and the Department of Biochemistry at LMU, have made progress in unraveling this complex activation process. Previous studies indicated that complex RNA molecules must be cleaved before the receptor can identify them. The researchers utilized various technologies to gain a deeper understanding of this mechanism.come in. Nucleases are enzymes that degrade RNA, and they play a crucial role in the processing of foreign RNA for TLR7 detection. The LMU researchers used a combination of cell biology and cryo-electron microscopy to study the mechanism by which single-stranded foreign RNA is processed by nucleases for recognition by TLR7. Their findings have been published in the journal Immunity.
The immune system has evolved to recognize pathogens from their genetic material
Over the course of evolution, the immune system has developed specialized mechanisms for recognizing and responding to pathogens based on their genetic material. For example, the innate immune receptor TLR7 is activated by viral RNA. Viral RNAs are long, complex molecules that are too large to directly interact with TLR7. This is where nucleases, which are enzymes that degrade RNA, come into play. The researchers at LMU used a combination of cell biology and cryo-electron microscopy to investigate how single-stranded foreign RNA is processed by nucleases to be detected by TLR7. Their findings have been published in the journal Immunity.
Molecular cutting tools known as endonucleases and exonucleases are used to chop the ‘RNA thread’ into small pieces. Endonucleases cut the RNA molecules through the middle like scissors, while exonucleases cleave the thread from one end to the other. This process creates various RNA snippets, which can then bind to two different pockets of the TLR7 receptor. The activation of both binding pockets by these RNA pieces initiates a signaling cascade that activates the cell and triggers an alarm state.
The researchers found that the recognition of RNA by TLR7 requires the activity of the endonuclease RNase T2 working in conjunction with the exonucleases.The enzymes PLD3 and PLD4, also known as phospholipase D3 and D4, were previously understood to be capable of degrading RNAs. However, according to Hornung, it has now been demonstrated that they interact with and activate TLR7.
Regulating the immune system
The researchers also discovered that the PLD exonucleases play a dual role in immune cells. When it comes to TLR7, they have a pro-inflammatory effect, but with another TLR receptor, TLR9, they have an anti-inflammatory effect. Bérouti explains that this dual role of PLD exonucleases indicates a carefully balanced approach to controlling appropriate immune responses.The enzymes’ ability to promote or inhibit inflammation may play a crucial role in protecting the system from dysfunction. Further research is needed to explore the potential impact of other enzymes on this signaling pathway and determine if the molecules involved could be targeted for therapy.
