Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript ‚Implication of the LRR domain in the regulation and activation of the NLRP3 inflammasome’ by Cescato et al. provides a very interesting, comprehensive and well-written overview on the role of the leucine-rich repeats found in the most studied inflammasome sensor protein Nlrp3. The authors put a lot of effort in providing an up-to-date review including extensive discussion of structural properties of the domain, various reported and tested isoforms of Nlrp3, post-translational modifications, and clinical relevance of the LRR domain. While the review article is well-suited for publication, the authors need to address a few points before publication:
While the article clearly focusses on Nlrp3, it would be very interesting to mention Nlrp10 in the main text, as it is the only NLRP without LRR. Recent work by
NLRP3 has an unusually high content of the redox-sensitive amino acid cysteine and provided both sequence alignments and structural details on the positions.
- Check the sentence: This review aims to provide a comprehensive overview of current knowledge and recent discoveries regarding the involvement of LRR NLRP3 domain in modulating NLRP3 inflammasome activation.
- Check the sentence: Considering that the physiological intracellular concentration of K+ is too high to active NLRP3 and that inhibiting K+ efflux prevents NLRP3 activation in both murine and human macrophages (75), it suggests that K+ efflux may be the critical convergence point for NLRP3 activation (29).
- Check the sentence: NLRP3 mutant lacking the LRR domain was unable to produce IL-1β following both the priming and activation steps.
Author Response
We thank reviewer 1 for all his comments, helping our manuscript to gain clarity.
Best regards.
Author Response File: Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsCescato M. et al, in the Review “Implication of the LRR domain in the regulation and activation of the NLRP3 inflammasome” clearly describe the structure and function of LRR domain highlighting its involvement in NLRP3 inflammasome activation and the impact of its mutations in pathological conditions.
The Review is well written, organized and focused. The Review is well referenced, and the Figures are fine prepared.
Minor:
1. I suggest improving the description of the different NLRP3 activation pathways (canonical, non-canonical, alternative) and add an explanatory figure of these pathways, to better focus the involvement of LRR in the regulation and activation of NLRP3 inflammasome.
2. The Authors said: “Furthermore, gain-of-function heterozygous variants in NLRP3 are associated with a rare monogenic auto-inflammatory disease called Cryopyrin-Associated Periodic Syndrome (CAPS) and characterized by systemic inflammation and various clinical features including mainly urticaria, arthromyalgia, buccal aphtous, and neuroinflammation with eye, hear and mengingitis involvement” Please add the specific bibliography.
3. Please check the title of Table 1.
4. Please check the fonts that appears to be different within the Review in all sections and notice that some figures are highlighted.
Author Response
We thank reviewer 2 for his comments, helping us to improve our manuscript.
Best regards.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThis is a very readable and informative review concerning the complex activation and interactions of NLRP3 and other NLR families, with a focus on the LRR domain. The role of PTM in activation/deactivation/regulation of NLRP3 is discussed very well. The Figures are of outstanding quality. Table 1 / Figure 7 is therapeutically very interesting, giving a summary of patients with CAPS, with their mutations in LLR. Overall, a very useful review for experts in this very active field, as well as scientists with an interest in inflammation.
Comments on the Quality of English LanguageEnglish is very good.
Minor suggestions:
p9, line 5: 'active' should be 'activate'
Font and size needs attention in abstract and introduction.
Author Response
Comment: p9, line 5: 'active' should be 'activate'. Font and size needs attention in abstract and introduction.
RESPONSE: We thank reviewer 3 for his comment. The spelling mistake was modified accordingly and the manuscript fonts are harmonized.