Venue suggestions (v1), IPO9 modulates histone-dependent inhibition of cGAS activity, In Silico

Venue Recommendations

as_is

bioRxiv (or equivalent preprint server)

This manuscript is already suitable for preprint circulation in its current form. The core contributions—target identification via chemical proteomics, the IPO9–cGAS–H2A-H2B axis, and the cryo-EM structure—are substantive and will be of immediate interest to the cGAS-STING and chemical biology communities. Preprint posting allows the work to establish priority and gather feedback while the authors address the editor's major-revision items. The In Silico review process itself (once completed) will add credibility to the preprint record.

after_revision

Nature or Science

Once the epistasis experiment (Required Revision #1) is completed and the cellular mechanism is either confirmed or appropriately reframed, this work will be competitive for a top-tier venue. The IPO9 discovery is genuinely novel, the H2A-H2B/NCP distinction is mechanistically important, and the chemical-proteomic target identification is exemplary. The cryo-EM structure, even at 4.3 Å, provides useful structural context. If the epistasis test shows that SR-218 activity is occluded by IPO9 depletion, the causal claim becomes airtight and the paper's impact is substantially elevated. If knockdown does not occlude activity, a reframed version emphasizing the biochemical and structural contributions (with IPO9 engagement as a correlate rather than the mechanism) is still strong enough for a top venue, though the framing will be more modest.

Acceptance odds after revision: 40–50% for Nature/Science, depending on epistasis outcome and reviewer appetite for the mechanistic ambiguity around displacement vs. sequestration.

Nature Structural & Molecular Biology or Nature Chemical Biology

These are realistic landing spots even if the epistasis experiment yields an unexpected result (e.g., SR-218 retains activity in IPO9-KO cells). The target-identification chemistry is alone publishable in Nature Chemical Biology, and the IPO9–cGAS axis is a solid structural biology contribution. The combination of chemical proteomics, biochemistry, and cryo-EM is well-suited to these venues' scope. Reframing to emphasize the biochemical discovery (IPO9 selectively reverses H2A-H2B but not NCP inhibition) and the structural model, with the cellular phenotype as supporting context rather than the lead claim, positions the work comfortably.

Acceptance odds after revision: 60–70%, particularly if the required revisions are thorough and the epistasis test is executed cleanly (regardless of outcome).

eLife

A strong fit for the revised manuscript. eLife values mechanistic clarity and candid discussion of limitations, both of which the authors already demonstrate. The three-mechanism framing (displacement, sequestration, DNA competition) is exactly the kind of honest uncertainty eLife rewards. The paper's scope—a new regulatory axis for a well-studied pathway, supported by solid biochemistry and structural biology—matches eLife's sweet spot. The required revisions (especially #1, #3, and #4) will strengthen the manuscript substantially without requiring new conceptual work.

Acceptance odds after revision: 70–75%.

alternative

Molecular Cell

If the top venues prove competitive or if the epistasis experiment yields results that require substantial reframing, Molecular Cell is a robust fallback. The IPO9 discovery and the H2A-H2B/NCP distinction are mechanistically important contributions to cGAS biology, and the chemical-proteomic target ID is methodologically sound. Molecular Cell has published related work on cGAS regulation and will value the specificity of the IPO9 axis. The cryo-EM structure, even at 4.3 Å with acknowledged limitations, adds value.

Acceptance odds: 65–75% after revision.

EMBO Journal

Another solid alternative if the epistasis test is inconclusive or if the authors prefer a venue with slightly lower impact-factor expectations. EMBO Journal values mechanistic work in cell biology and structural biology, and the IPO9–cGAS axis is a genuine advance in understanding cGAS compartmentalization and regulation. The chemical-proteomic discovery is a strong methodological contribution.

Acceptance odds: 60–70% after revision.

Preprint + specialized workshop or journal club

If the authors wish to accelerate dissemination while completing the major revisions, posting to bioRxiv and presenting at a cGAS-STING or chemical biology workshop (e.g., Gordon Research Conference on Innate Immunity, or a medicinal chemistry symposium) will establish priority and gather expert feedback. The In Silico review, once published, will serve as a public peer-review record and enhance the preprint's credibility. This is a low-risk path that does not foreclose submission to top venues later.

Notes on fit and strategy

The epistasis experiment is the pivot point. If SR-218 activity is abolished in IPO9-KO cells, the paper becomes a clear fit for Nature/Science and the causal claim is unambiguous. If knockdown does not occlude activity, the work is still publishable at high-tier venues but requires reframing to emphasize the biochemical discovery (IPO9 reverses H2A-H2B inhibition) and the structural model, with the cellular phenotype as a correlate. Either outcome is scientifically interesting; the framing must match the evidence.
The cryo-EM resolution is not a barrier. 4.3 Å is sufficient for secondary-structure assignment and docking of higher-resolution coordinates. The authors' candid discussion of resolution limits is appropriate. Requalifying the residue-level contact claims (Required Revision #4) will address the main concern here.
The target-identification chemistry is the paper's strongest element and is alone sufficient for publication at a specialized venue (Nature Chemical Biology, Chemical Science). The combination with biochemistry and structure elevates it to a broader audience.
Avoid In Silico as a primary target. In Silico is an overlay journal that reviews preprints; it is not a traditional submission venue. The authors should post to bioRxiv (or similar) and then submit to In Silico for review if they wish a public peer-review record. Alternatively, submit directly to a traditional venue (Nature, eLife, Molecular Cell, etc.) and use the In Silico review as a post-hoc credibility layer if desired.