Talk:WikiJournal of Science/RIG-I like receptors
WikiJournal of Science
Open access • Publication charge free • Public peer review • Wikipedia-integrated
Previous
Volume 1(1)
Volume 1(2)
Volume 2(1)
Volume 3(1)
Volume 4(1)
Volume 5(1)
Volume 6(1)
This article has been through public peer review.
Post-publication review comments or direct edits can be left at the version as it appears on Wikipedia.First submitted:
Accepted:
Article text
PDF: Download
DOI: 10.15347/wjs/2019.001
QID: Q62604415
XML: Download
Share article
Email
| 
Facebook
| 
Twitter
| 
LinkedIn
| 
Mendeley
| 
ResearchGate
Suggested citation format:
Natalie Borg (2019). "RIG-I like receptors". WikiJournal of Science 2 (1): 1. doi:10.15347/WJS/2019.001. Wikidata Q62604415. ISSN 2470-6345. https://upload.wikimedia.org/wikiversity/en/3/32/RIG-I_like_receptors.pdf.
Citation metrics
AltMetrics
Page views on Wikipedia
Wikipedia: Content from this work is used in the following Wikipedia article: RIG-I-like receptor.
License: 
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction, provided the original author and source are credited.
Joanna Argasinska 
(handling editor) contact
Konrad Förstner (handling editor) contact
Teunis B H Geijtenbeek
Ying Kai Chan
Article information
Plagiarism check
Pass. WMF copyvio tool using TurnItIn. Only trivial duplication such as affiliation address were detected and are not regarded as plagiarism. T.Shafee(Evo﹠Evo)talk 23:08, 10 December 2018 (UTC)
First peer reviewer
reviewer-annotated pdf
Review by Teunis Geijtenbeek , University of Amsterdam
These assessment comments were submitted on , and refer to this previous version of the article
The review describes the role of Rig-I like receptors (RLR) in virus infections. It summarizes their regulation and function also how viruses hijack the receptors.
Unfortunately, the review is not very timely as it discusses studies that have been published quite some time ago. No recent studies are included in the review, even though we know currently much more about RLRs, how they are regulated and their function in virus infections. Moreover, the review only addresses only ubiquitination as a regulation mechanism but RLRs are regulated at very different levels including dephosphorylation. This needs to be discussed.
- Comments
Overall, the review refers to many ‘old’ references and new studies need to be included. This is very relevant due to several recent new insight into these receptors.
See responses below for the relevant updates that reference more timely references.
First paragraph. Include expression pattern of these receptors and change sentence concerning soluble PRRs as RLRs are cytoplasmic RLRs.
As requested I now include the following in the first section titled ‘RIG-I like receptors’:
‘The RLR receptors provide frontline defence against viral infections in most tissues.’ ‘…this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection.’
The review needs to clearly discuss what viral RNA structures are recognized. In the RIG-I ligand section it is stated that Dengue and West Nile virus are recognized by this is only after replication so incoming RNA is not recognized.
The RNA structures recognized by RIG-I, MDA5 and now LGP2 are noted in the section titled ‘RLR ligands’.
The following has also been omitted to ensure the accuracy of the review, whilst retaining its simplicity:
‘Although RIG-I and MDA5 respond to distinct viruses, there are cases where their specificity overlaps. For example, both RIG-I and MDA5 respond to dengue virus and West Nile virus, which are both Flaviviruses (Fredericksen et al, 2008; Loo et al, 2008; Nasirudeen et al, 2011) , and their role, at least in West Nile virus infection is complementary (Errett et al, 2013) .’
Mention what viruses are recognized by LPG2
The section titled ‘RLR ligands’ now states that LGP2 recognises picornaviruses:
‘The latter is linked to LGP2’s recognition of picornaviruses (e.g. encephalomyocarditis virus) (Satoh et al, 2010) , as per MDA5.’
The family is usually referred to as the Dead box helicase family due to Asp-Glu-Ala-Asp sequence
The reviewer is correct in noting that RIG-I (DDX58) belongs to the DEAD Box helicase family, however unlike other family members it does not contain the characteristic DEAD (Asp-Glu-Aala-Asp) motif, but rather a DECH motif. To clarify this the review now states:
‘The RLR receptors are members of the DEAD-box helicase family (despite containing a DExD/H motif, rather than the DEAD motif characteristic of the family) and share a common domain architecture.’
Wies et al immunity 2013 have shown that both mda-5 and rig-I need to be dephosphorylated by PP1α and PP1γ for activation. Several viruses are able to prevent dephosphorylation, thereby escaping antiviral immunity (such as measles). This should be mentioned as it is vital to its function
I have now included this information in the section titled ‘Regulation of RLR signaling’:
‘Upon viral infection RIG-I is dephosphorylated by PP1 and PP1 (Wies et al, 2013) , permitting the ubiquitination of the RIG-I CARD domain by the E3 ligase TRIM25 to activate the RLR-mediated antiviral immune response (Gack et al, 2007) . Given post-translational modifications are so pertinent to the activation of RLR signaling, it is not surprising that they are directly, or indirectly, targeted by viruses such as influenza A (Gack et al, 2009) and measles (Davis et al, 2014) , respectively, to suppress signaling. (Figure 2).’
MAVS forms a signaling platform in which TRFA3, TBK1 and IKKε are recruited and signaling occurs. This could be mentioned. It is not only the multimerization that leads to activation of transcription factors.
The section titled ‘RIG-I antiviral signaling’ has been extended to include this information:
‘This binding event is essential to signaling as it causes MAVS to form large functional aggregates in which TRAF3 (TNF receptor-associated factor 3) and subsequently the IKKe/TBK1 (I-kappa-B kinase-epsilon/TANK-binding kinase 1) complex are recruited. The IKK/TBK1 complex leads to the activation of the transcription factors interferon regulatory factor (IRF)-3 and IRF7 which induce type I (including IFN and IFN) and type III interferons (IFN) (Figure 2).’
The author states that IFN by themselves are antiviral. This is not correct (or a reference should be included). IFNs induce signaling via IFNReceptor and this leads to activation of specific antiviral programs.
The sentence eluding to IFNs being themselves antiviral has been removed. See immediately below for the information related to the IFN receptor.
The sentence ‘Overall this causes the death of infected cells, the protection of surrounding cells and the activation of the antigen-specific antiviral immune response’ is unclear. Explain how IFN plays a role in this (by inducing IFNR signalling in other cells).
To clarify this sentence, the sentence before it now reads:
‘The type I IFNs bind type I IFN receptors on the surface of the cell that produced them, and also other cell types that express the receptor, to activate JAK-STAT (Janus kinase/signal transducers and activators of transcription) signaling. This leads to the induction of hundreds of interferon stimulated genes (ISGs) that amplify the IFN response.’
Extend the section on regulation of RLR by including new insight such as dephosphorylation and how this is prevented by certain viruses such as Measles virus.
I have incorporated these suggestions in the section titled ‘Regulation of RLR signaling’. The latter part of that section now reads:
‘Upon viral infection RIG-I is dephosphorylated by PP1 and PP1 (Wies et al, 2013) , permitting the ubiquitination of the RIG-I CARD domain by the E3 ligase TRIM25 to activate the RLR-mediated antiviral immune response (Gack et al, 2007) . Given post-translational modifications are so pertinent to the activation of RLR signaling, it is not surprising that they are directly, or indirectly, targeted by viruses such as influenza A (Gack et al, 2009) and measles (Davis et al, 2014) , respectively, to suppress signaling. (Figure 2).’
The last section on hijacking is very dated and new studies should be included. For example: Dengue NS4A binds to MAVS and thereby prevents the interaction between RIG-I and MAVS. NS2B3, NS2A and NS4B target RIG-I and MDA5 signaling via inhibition IKKε. West Nile virus also Targets RIG-I and MAVS signaling e.g. Zhang H.L. 2017
I have updated the ‘Viral hijacking of RLR signaling’ section. The relevant additions include:
1) ‘Likewise, dengue virus (DENV) uses its NS2B3, NS2A and NS4B proteins to bind IKK and prevent IRF3 phosphorylation (Anglero-Rodriguez et al, 2014; Dalrymple et al, 2015) and its NS4A protein, as per the zika virus, to bind MAVS to block RLR receptor binding (He et al, 2016; Ma et al, 2018) .’
2) ‘For example, influenza A virus and West Nile virus (WNV) use their NS1 (nonstructural protein 1) proteins to block RIG-I ubiquitination by TRIM25, or cause RIG-I degradation, respectively, which in turn inhibits IFN production (Gack et al, 2009; Zhang et al, 2017) ’.
Furthermore, there is no concluding section which would strengthen the review.
I have added a ‘Summary’ section as requested.
There are many mistakes (typo) and form errors (viruses with Capitals etc) so please edit the review carefully and adhere to standard writing forms.
I have corrected these errors and thank the Reviewer for pointing them out.
Second peer reviewer
reviewer-annotated pdf
Review by Ying Kai Chan , Harvard Medical School
These assessment comments were submitted on , and refer to this previous version of the article
In this review article. Dr. Borg provides a short and succinct snapshot of how RIG-I like receptors (RLRs) function as the frontline defense against viral infections. She reviews the RNA ligands recognized by RLRs, structural features of the RLR proteins, and how RLRs signal (or fail to signal) during viral infections.
The review article is written in a clear and understandable fashion and should be of interest to those in the field of innate immunity. Key signaling events are summarized in a concise fashion so that the reader grasps critical concepts in RLR activation. Select examples of how viruses antagonize RLR are also provided, which lends the article medical relevance.
I would suggest the possibility of adding more figures to make the article stand out even more. For example, a schematic figure of RLR signaling, overlaid with viral antagonism, would be quite complementary to the article.
I now include an additional figure, Figure 2, depicting a schematic of RLR signaling, which includes viral antagonists relevant to the text.
In addition, here are a few minor points:
- Reference “Saito nature 2008 523” not cited in references
The Saito reference is now included in the reference list.
- Page 1 typo: “Distinct RNA-binding loops within the CTD of three RLRs dictate the type of RNA they can bind”
The Page 1 ‘typo’ has been corrected and now reads:
‘Distinct RNA-binding loops within the CTD of the three RLRs dictate the type of RNA that they can bind (Takahasi et al, 2009) .’
- Page 2 terminology: I suggest calling out “post-transcriptional modification” instead of just terming it “modification” (e.g. “CARDs can undergo modifications, “CARDs of MDA5 are modified as a means of regulating signaling”) to avoid ambiguity
Any reference to ‘modification’ has been changed to ‘post-translational modification’. For example:
‘As a safeguard for RLR activation, the exposed RIG-I and MDA5 CARDs can undergo post-translational modifications (e.g. ubiquitination, phosphorylation) that either positively or negatively regulate downstream signaling.’
- Page 3 terminology: Regarding HCV NS3/4A, I recommend calling it “cleaving” rather than “removing” a part of MAVS
The terminology has been updated and ‘remove’ has been replaced with ‘cleaves’:
‘This outcome is also achieved by the hepatitis C (HCV) NS3/4A protein by cleaving a part of MAVS (Li et al, 2005) (Figure 2), and the foot-and-mouth disease virus (FMDV) leader protease (Lpro) which cleaves LGP2 (Rodriguez Pulido et al, 2018) .’