In all eukaryotes, ER-quality control processes prevent the secretion of mutant glycoproteins which could have adverse consequences for cells and whole organisms. Some misfolded glycoproteins may, however, still be functional and their release from ERQC to other compartments of the secretory pathway could be a means to overcome certain diseases. This possibility to rescue “responsive mutant glycoproteins” is still poorly investigated.
In this study, the authors advance the field and show by different approaches that UGGT deficiency can rescue the secretion of a misfolded glycoprotein in mammalian cells. Overall, the study is quite clear, and the data are well presented. I have some minor issues that should be addressed.

It is quite interesting that an active UGGT enzyme is required for retention of the misfolded glycoprotein in the ER as the misfolded glycoprotein still reaches the cellular membrane in the UGGT D1454A complemented line. The membrane localisation of the WT glycoprotein was unaffected in UGGT deficient cells and the glucosylation assays shows that the WT protein is also a UGGT substrate, which is not retained. How does the ERQC distinguish between these two proteins?

In the CRT-pull down in Figure 4 there are double bands visible. For the WT protein the intensity of the lower band appears higher, while for the mutant protein the intensity of the two bands is more similar. Could this represent differences in the number of attached N-glycans? The introduced mutant is close to an N-glycosylation site. The alg6 mutant may also cause changes in the glycosylation efficiency. Was the CRT-pull down also done in WT cells? Is there also a double band?

Related to the data in Figure 5: 5A basically shows that the YFP-signal intensity is increased for the mutant compared to the WT protein. How were the signals normalized on the blot? What is the effect of TCEP? In 5B there is a difference between WT and the mutant, but not in UGGT-deficient cells. Does this mean that UGGT activity does not contribute to improve the disulfide bond formation?

Introduction, page 4: The term “Caucasian” should not be used anymore.
Introduction, page 5: change inhuman to in human.
Results, page 5: ”and the mutation affects only…” – remove “only”.
Figure 4: why are their two bands in the whole cell lysate?
Figure 4E legend: change to “Quantification of blots from (C)” instead of (B).
Figure 5 legend: remove “)” after (A) and “.” at the end, change abeance to absence.

My minor concerns have all been addressed in the revised version of the manuscript and I have no further suggestions for improvement.