Induction of transposable element expression is central to innate sensing
Rookhuizen D.C. et al. (BioRxiv) DOI: 10.1101/2021.09.10.457789
Pathogen associated molecular patterns
The authors find that mouse dendritic cells upregulate transcription of all three major classes of transposable elements (LTR, LINE, and SINE) in response to stimulation by a TLR4 agonist, lipopolysaccharide. Focusing on LINE1 elements, they show that this effect is due to an LPS-induced loss of the SUV39H1 protein, a histone methyltransferase that marks DNA regions for transcriptional repression. Using Suv39h1 knockout and overexpressing cells, they observe that SUV39H1 levels calibrate the strength of the interferon response to LPS, with higher levels resulting in dampened signalling. Remarkably, they demonstrate that this is because LINE1 transcripts generated as a result of SUV39H1 loss undergo retro-transcription, and the resulting DNA or DNA:RNA hybrids are recognized by the cGAS/STING cytosolic DNA sensing pathway. A full-strength interferon response to LPS is thus shown to require DNA sensing, a surprising result but one that fits with existing data suggesting that cGAS/STING activation is required for optimal innate responses to certain RNA viruses. Indeed, looking at one such virus, influenza A, the authors recapitulate their main findings by showing that (1) overexpression of Suv39h1, (2) suppression of LINE1 element transcription, (3) suppression of reverse transcription, or (4) STING inhibition all result in a less-effective innate response to the virus.
Based on these findings, the authors propose a model in which initial recognition of a pathogen associated molecular pattern (PAMP) triggers expression of transposable elements, which effectively serve as additional PAMPs. The authors suggest the term TRAMPs (“TRAnsposable element Molecular Patterns”) for these host-derived PAMPs. At a critical threshold of interferon activation, TRAMP recognition might be self-amplifying and ultimately drive much of the interferon response to an initial PAMP.
Is cGAS absolutely required for a TLR4-driven interferon response? In the RAW264.7 macrophages, cGAS deletion nearly completely abrogates the interferon response to LPS (Fig. 4D), whereas STING blockade only dampens the response in the dendritic cells (Fig. 4B). To make sense of this it might be helpful to see the knockout results quantified relative to the untreated condition for each knockout cell line, since (as the authors note) the knockouts may have reduced levels of tonic interferon signalling. Additionally, in the influenza model, it would be helpful to see the effect of the various perturbations (e.g. SUV39H1 overexpression) on ISG induction. At a higher level, only limited data is presented for human cells, and it is not clear to what extent TRAMPs are involved in the type I interferon response in non-immune cells. Finally, the mechanism for SUV39H1 depletion in response to LPS was not investigated here and remains an important follow up question.
The narrow observation that TLR4 stimulation induces expression of transposable elements is novel and raises interesting mechanistic questions. More importantly, however, this preprint argues that transposable element expression is a key amplifying step in interferon pathway activation. If this model holds up in other settings, it will represent a conceptual advance in how we think about innate immune activation and calibration, with implications for the management of autoimmunity, aging, infection, and cancer. For example, inhibitors targeting the LINE-1 reverse transcriptase or the cGAS/STING pathway may have wider application for the management of innate immune activation than previously thought. Drugs that cause tumors – or nearby immune cells – to express transposable elements may stimulate interferon pathway activation and tumor clearance. These are not new ideas, but the model suggested by the authors unifies diverse observations and may prove to be a paradigm shift. This work is also of interest beyond the immunology community as it is the latest in a series of advances identifying important functional roles for what was once considered “junk” DNA.
Reviewed by Tim O’Donnell as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.