Status lab-led for Eggenberger 2019 and for the tenOever 2016 Perspective, which is single-authored and synthesises work largely belonging to other groups. Paget 2023 is collaborative and was led by the Hur laboratory at Harvard with Sun Hur as sole corresponding author, and the tenOever contribution there is recorded as provision of reagents, so that discovery is not this program's Areas Innate Immune Signaling and the Interferon Response, Small RNA Biology and the Limits of Antiviral Silencing
Pluripotent cells were the standing exception to the claim that the type I interferon system is available to any vertebrate cell, and the explanations offered had all addressed how the response is absent rather than why the system is unused. Reframing the question as compatibility changes what must be measured, from what blocks the response to what engaging it would cost.
Eggenberger 2019 built an internal comparison by reprogramming human primary fibroblasts to induced pluripotent cells and redifferentiating them, so that two states of one genetic background could be set side by side. Only the pluripotent state failed to respond to 5 prime triphosphate RNA, to interferon beta or to influenza A virus lacking NS1, and redifferentiation restored responsiveness, which excludes clonal selection. Mouse embryonic stem cells behaved the same way. Co-expression of OCT4, SOX2 or KLF4 with a constitutively active IRF7 in competent cells repressed IFIT1 and ISG15 induction, with KLF4 most potent. The consequence side is the substantive result. A forty-eight hour pulse of a truncated IRF7 that bypasses kinase activation left roughly 2,000 genes differentially expressed five days later, after IRF7 and its direct targets had returned to baseline, with NANOG and IDO1 dysregulated and subsequent differentiation compromised for ectoderm and endoderm and distorted within mesoderm.
The restraint side of the same argument comes from work led elsewhere. Paget 2023 tested the prevailing reading that stress granules are signalling platforms for RIG-I-like receptors and found the opposite, using three genetically distinct routes to granule deficiency. All three showed stronger signalling to a defined double-stranded RNA at the level of transcriptome, cytokine messenger RNA and protein, IRF3 activation and cell-free MAVS signalling potential, and granule-deficient cells underwent caspase-dependent apoptosis largely rescued by deleting MAVS but not IRF3. Restoring granules in PKR-deficient cells suppressed signalling, and the protection extended to endogenous double-stranded RNA accumulating after ADAR1 knockdown.
What is now known is that the antiviral transcriptional program is not cost-free and is not compatible with every cell state, and that unbuffered detection of double-stranded RNA is lethal through MAVS independently of interferon. What is not known is whether the program is incompatible with pluripotency in a developing organism, since all of Eggenberger 2019 is in vitro with an artificial driving construct at one dose and duration, and how granules suppress signalling, which the authors of Paget 2023 state is unresolved. The broader proposal that chordates lost RNA silencing through incompatibility with interferon rather than through redundancy is labelled an attractive hypothesis by tenOever 2016, whose supporting evidence is correlative and largely other laboratories' work, and no later publication in this corpus returns to pluripotency.
Substantiated by - Type I interferon response impairs differentiation potential of pluripotent stem cells, forces the program into cells that cannot otherwise run it and measures lasting transcriptional change and compromised germ layer potential - Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA, led by the Hur laboratory, reverses the reading of stress granules and shows that unbuffered double-stranded RNA sensing kills through MAVS - The Evolution of Antiviral Defense Systems, single-author Perspective supplying the framework in which two antiviral systems can be mutually incompatible
Stress granules restrain rather than amplify double-stranded RNA sensing, and cells lacking the granule nucleators G3BP1 and G3BP2, UBAP2L or PKR respond to double-stranded RNA with excessive RIG-I-like receptor, PKR and OAS activation and MAVS-dependent apoptosis.
Forcing an interferon-stimulated gene program in human induced pluripotent stem cells with a constitutively active IRF7 produces lasting transcriptional change and impaired germ layer differentiation, supporting the proposal that the canonical type I interferon system and pluripotency are difficult to hold simultaneously.
A synthesis arguing that antiviral defenses across the three domains of life reuse a small set of designs, antisense recognition joined to nuclease activity and later to transcriptional and secreted responses, and proposing that chordates lost RNA interference through incompatibility with interferon.