Septins in Infections: Focus on Viruses

Round 1

Reviewer 1 Report

The review article of Henzi T and co-authors summarises and analyses the functions of scaffolding proteins septins in pathogenesis of the infectious diseases. This review is well-written and contains analysis of the published data, which makes it interesting for the readers. However, it also contains unpublished data by the authors, which in my opinion, does not fit into the format of review publication. I have the following major comments for this review:

 

1. For the person with no background in septins, it is rather hard to understand how structure of septin molecules determines their functions from simply reading the description. I suggest including the figure which shows domain organisation of septin molecules and their 3D-structure to illustrate the text in lines 32-41.
2. Authors need to consider that ZIKV NS2BNS3 protease domain fusion protein (lines 245-254) is an artificial chimera, which does not exist in real viral infection. Does the activity of this fusion translate into the activity of heterodimer? It also appears to me that the authors of the original manuscript [49] came to the different explanation for the functional implication of septin cleavage by ZIKV NS3 and linked it to cytokine production, which is not mentioned in this review. Can authors clarify this?
3. Lines 256-259 and Fig 1 represent unpublished data by the authors, which is not normally permitted in reviews. Considering that the manuscript does not provide sufficient information on how this experiment was conducted, this data cannot be peer-reviewed. Authors should consider publishing this separately in a research article format.  

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

In the review article entitled Septins in virus infections, the authors describe some aspects of septin biology, with focus on infections including virus infections. I have the following general statements on the manuscript

1. In general, for many statements’ citations provided are review articles, more original citations need to be made
2. Addition of unpublished data in a review article is also not standard practice and I am not sure whether acceptable. The observation in the authors lab can best be stated as “unpublished data”
3. Out of approx. 290 lines in the main text, less than half (including original data) deals with viral infections. Hence the title is rather misleading. The title should at least be changed to “Septins in infections: focus on viruses”
4. The summary and conclusions section has too many redundancies with the other parts and is unwanted word count.

 

Specific comments

1. Line 25: The nomenclature of septin genes have recently been changed to SEPTIN instead of “SEPT”
2. Line 43-45 please change as: A basic hexameric unit consisting of septins in the order of SEPT7– SEPT6–SEPT2–SEPT2–SEPT6–SEPT7 was initially described by Sirajuddin et al. [10].
3. Line 56: this statement is trivial as there are more than one septin interactome studies published
4. Line 66: There are additional recent citations on septins in exocytosis / degranulation
5. Line 16: Please cite papers which show septin dysfunction in diseases
6. Line 131-133: I am unable to understand the statement. Are the authors stating that since 7% bacteria survive, septin cages are inefficient?
7. The viral infection section needs to be better presented with subsections for

• VACV infection
• HCV infection
• Human and avian influenza
• HHV8/KSHV
• Zika virus

This can be further supported by a diagrammatic view on the different roles of septins in the viral life cycle

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Septins are not often described in the literature. Authors presented good review about septins, giving their activity in viral infections. I suggest some corrections:

1. Please add figure of 3D structure of one of septins.
2. Please, draw scheme/figure of mechanisms of action /pathways of septins activity.
3. Lines 112 and 121 - all names of organisms (e.g. M. oryzae, Shigella, Listeria, Salmonella) should be italics.
4. Line 127 - lack of symbol in TNF-.
5. Figure 1 is original made by authors of this manuscript? When not, please add citation, and should be also permission for figure reproduction.
6. Lines 240 and 242 - lacks of k in NF-kB.
7. Conclusions should be as short (some sentences) separate chapter.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Authors have addressed all my comments.

Author Response

We have addressed all the comments of reviewer 1 in round 1.

Reviewer 2 Report

In the review article entitled Septins in virus infections, the authors describe some aspects of septin biology, with focus on infections including virus infections. The revised manuscript has been improved with incorporation of suggestions from both referees. I have still some comments and suggestions to make the review publishable/citable.

1. Figure 1 is not cited in text. May be cite in paragraph 2 and 3)
2. Line 29: Please use “transcripts” rather than “transcript isoforms”
3. Line 79: if you do not have a citation to give, please avoid this statement that septin dystfunction is linked to wide variety of diseases. Septin expression correlating to some pathologies cannot be taken as proof of dysfunction.
4. For the next line (line no 80, give citations for the KO phenotype papers)
5. Line-96: To be clear about the statements in the cited paper, change “phagocytosis by..” to “antibody-mediated phagocytosis by…”
6. Line 109 to 112: these statements are not valid. Since recent studies have clearly established a role for septins in mitochondrial dynamics, these cannot be stated this way. What is the basis for telling that the phenoypes using low FCF concentrations is still septin independent? There should be balanced take on this topic based on the two EMBo publications on mitochondrial dynamics and Septins.
7. Line 130: make the statement balanced. The role for septins could be anti or pro infection. Other than the cited septin cages, there are papers like PMID: 29885024, 19145258, 21504731 etc which show a role for septins in bacterial entry into host cells.
8. Line 131: I don’t think salmonella replication happens in cytosol. This bacteria survives in the endosomes like Mycobacteria
9. Line 169: change septin to septins
10. In  the same line “Infection of cells with A36-YdF virus, a vaccinia strain unable to induce actin tail formation, strongly increases colocalization of septin 7 with CEV, indicating that septin recruitment interferes with actin tail formation and/or stimulates removal from the virions”. This line is not clear.
11. Line 247: Change the tilte to Human Herpses Virus 8 (Kaposi Sarcoma associated Herper Virus)
12. Section 3.5 and 3.6 combine as “3.5. Flaviviruses”. Make the Zikavirus paragraph as the first para under this head. Add the second paragraph about own unpublished data/JEV after that (obviously with changes to first sentences for both paragraphs). One cannot give first chance/prominence to unpublished data over published ones.
13. Line 282: I am not sure whether there are enough PTMs known/characterised for septins as expected from the number of genes or in comparisons to similar networks like keratins. Better to state” The 13 human septin geness together with alternative splice variants, tissue specific expression and possible post-translational modifications create a complex cytoskeletal network with huge diversity”.
14. Line 289: what do you mean by “ectopic expression”? I am not sure whether this term is acceptable in case of a ubiquitous proteins like septins.
15. Kines 290-92, change to “Viral infections strongly alter the expression levels of a large number of genes [65-67] and members of the septin family are also found among those proteins.”
16. I still believe that the discussion is mostly redundant and largely speculative. Since this is a second round of revision, I would like to propose the following text for the lines from 299-320, so that no more time is lost

“Septins may contribute to several steps of the virus replication cycle. Septin scaffolding platforms might be important for the recruitment of receptors to the cell surface during virus docking. Phagosomes equipped with particular septins possibly act as an entry mechanism for microorganisms or could be involved in intracellular transport. Invasion of pathogens triggers a range of cellular defense mechanisms. One strategy is the aggregation of septin filaments around infectious particles [48]. These structures may help with the elimination of the infectious agent by scaffolding the autophagy ma chinery around the pathogen [31]. However, more research is needed to fully understand the septin code [13] with its transcript diversity, the subcellular distribution of the various isoforms, the existence of hexa- or octameric complexes and the diverse higher-order structures. Development of small molecules disturbing the function or structure of septins may provide a possible target for anti-viral therapies. Due to the multiplicity of septins functions, direct targeting could have many side effects. Therefore, septin-specific and function-specific targeting would be needed. An alternative therapeutic approach might aim at the perturbation of the subcellular localization of septin filaments [63].”

17. Considering the fact that there is no data now and based on the journal policy, the acknowledge section can be modified.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Authors corrected article according to reviewers' suggestions.

Author Response

We have addressed all the comments of reviewer 3 in round 1.