NOTCH signaling in Drosophila: disulfide bonds introduced by both Ero1L and QSOX3!
The paper: Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster.
Tien AC, Rajan A, Schulze KL, Ryoo HD, Acar M, Steller H, Bellen HJ.
J Cell Biol. 2008 Sep 22;182(6):1113-25. [Link to Article]
This paper concerns the Drosophila Notch receptor, whose extracellular domain contain 36 epidermal growth factor domains (EGF; with a total of 108 disulfides) and 3 Lin/Notch repeat domains (LNR; with a total of 9 disulfides). This multiplicity of disulfide bonds is likely to make Notch a sensitive indicator of impaired oxidative protein folding. Surprisingly, Tien et al. suggest that the EGF disulfides are not generated by Drosophila Ero1L, but by one of the three QSOXs in the fly (the other two QSOXs have an almost exclusive location in the male accessory glands). In contrast, the LNR disulfides are believed to be generated by Ero1L. The suggestion that different domains in the same protein are serviced by distinct sulfhydryl oxidases introduces a new level of complexity to oxidative protein folding!
Bellen and coworkers write:
“It is surprising that Ero1L, a thiol oxidase proposed to be involved in global disulfide bond formation in yeast, does not cause cell lethality in Drosophila. How do disulfide bonds form in the absence of Ero1L? We explored the possibility that other thiol oxidases (QSOX) are involved in ER disulfide bond formation. Although compromising QSOX does not cause a visible phenotype, genetic interaction between Ero1L and QSOX1 (CG4670) suggests that a QSOX protein can indeed contribute to disulfide bond formation when Ero1L function is decreased. Together with the strong UPR observed in Ero1L mutant cells, we propose that the UPR can either enhance the expression of QSOX or potentiate similar proteins at a later developmental phase. This also suggests that regulation of thiol oxidases in multicellular organisms is more complex than in yeast.”