More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins
Round 1
Reviewer 1 Report
A very detailed review of the literature on this subject was made and it could be interesting to scientists in the field.
However, I would suggest several minor improvements. First, as the paper describes so many different modulators a graphical abstract, that in a simple way summarizes the whole complex mechanism of SOCE regulation, would be appreciated. This figure could present the mechanism of CRAC activation cascade, and possible ways of regulation this cascade by different group of modulators.
Both sections: Positive modulators of SOCE and Negative modulators of SOCE start with the figure. I would recommend one or two sentences of an introduction to those parts and the annotations to the figure, as I haven’t noticed any in the main text. Also, it would be more comfortable for the reader if those modulators were presented in a more organized way, maybe add some subsections based on the interaction site of particular modulators. Also, some regulators described in previous section (like Cav1 or septins) are also positive/negative regulators, so the annotation to a certain figure should be added.
The table could be better presented. The regulators in the Table should appear in the same order as in the text, for example, UBQLN1 should be listed after EB1 and APC.
Author Response
We thank the reviewer for her/his positive comments.
We have now included a graphical abstract schematically summarizing the different steps of the CRAC activation cascade, including positive and negative regulators (lines 11-13).
Furthermore, sections ‘positive and negative modulators of SOCE’ now start with introductory sentences followed by the respective Figures (Figure 1 and 2, respectively). We have included Figure annotations throughout the manuscript.
Table 1 was adjusted and now lists all regulators in order of appearance.
Reviewer 2 Report
This article reviews the various regulatory proteins associated with the pore forming Orai. The written english is acceptable, and the references are appropriate. Below I list a few suggestions to improve the manuscript.
A large number of regulatory proteins are covered in detail, and a figure that provides a picture of the pathways and mechanisms would be helpful. An introductory figure outlining the CRAC cascade would also help the reader.
Is Table 1 composed only of proteins that directly bind Orai and STIM1? Is there a similar table for the regulatory proteins that do not directly interact with Orai and STIM?
Do the lines 322-323 "The promotion of SOCE by Cav1 was alternatively proposed..." have a reference (#61?)?
Lines 961-966 is a run on sentence and should be shortened.
Author Response
We thank the reviewer for her/his positive comments.
We have now included a graphical abstract schematically summarizing the different steps of the CRAC activation cascade, including positive and negative regulators (lines 11-13).
Table 1 was adjusted and now lists all regulators in order of appearance. We did not include an extra Table listing regulators that do not directly interact with STIM1/Orai1 as they are already included in Table 1 (SNAP-25, RTN4, JPH1/2).
Reference #61 now changed to #62 and indeed corresponds to "The promotion of SOCE by Cav1 was alternatively proposed...". This has been changed accordingly in the text (line 358-359).
Long sentences within the discussion/outlook have been shortened (now lines 1060-1067).
Reviewer 3 Report
The review manuscript by Berlansky et al discusses the molecules regulating store-operated CRAC channels. The review is very detailed and touches upon important topics such as cell-specific expression patterns of some of the regulatory proteins as well as the relevance of published findings under physiological conditions. The review is well written and ready for publication in the Journal.
Author Response
We thank the reviewer for her/his very positive comments!
