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Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster

¹ Program in Developmental Biology, ² Department of Molecular and Human Genetics, ³ Howard Hughes Medical Institute, and ⁴ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
⁵ Department of Cell Biology, New York University School of Medicine, New York, NY 10016
⁶ Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065

Correspondence to Hugo J. Bellen: hbellen{at}bcm.tmc.edu

Notch-mediated cell–cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1–like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor.

Abbreviations used in this paper: AMS, 4-acetamido-4'-maleimidylstilbene-2,2'-disulfonic acid; AP, anterior posterior; APF, after puparium formation; Ci, cubitus interruptus; Dl, Delta; Dpp, decapentaplegic; dsRNA, double-stranded RNA; DV, dorsal ventral; Ero1L, ER oxidoreductin 1–like; ESO, external sensory organ; ey-FLP, eyeless-flipase; Hh, hedgehog; LNR, Lin12-Notch repeat; MARCM, mosaic analysis with a repressible cell marker; NECD, Notch extracellular domain; NEXT, Notch extracellular truncation; PBST, PBS-Tween; PDI, protein disulfide isomerase; QSOX, quiescin/Sox; SOP, sensory organ precursor; UPR, unfolded protein response.

© 2008 Tien et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Tien, A.-C., Rajan, A., Bellen, H. J. (2009). A Notch updated. JCB 184: 621-629 [Abstract] [Full Text]  

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