Cruz-Garcia, DavidBrouwers, NathalieDuran, Juan M.Mora, GabrielCurwin, AmyMalhotra, Vivek2023-12-112023-12-112017Cruz-Garcia D, Brouwers N, Duran JM, Mora G, Curwin AJ, Malhotra V. A diacidic motif determines unconventional secretion of wild-type and ALS-linked mutant SOD1. Journal of Cell Biology. 2017 Sep 4;216(9):2691-700. DOI: 10.1083/jcb.2017040560021-9525http://hdl.handle.net/10230/58487The nutrient starvation-specific unconventional secretion of Acb1 in Saccharomyces cerevisiae requires ESCRT-I, -II, and -III and Grh1. In this study, we report that another signal sequence lacking cytoplasmic protein, superoxide dismutase 1 (SOD1), and its mutant form linked to amyotrophic lateral sclerosis (ALS), is also secreted by yeast upon nutrient starvation in a Grh1- and ESCRT-I–, -II–, and -III–dependent process. Our analyses reveal that a conserved diacidic motif (Asp-Glu) in these proteins is necessary for their export. Importantly, secretion of wild-type human SOD1 and the ALS-linked mutant in human cells also require the diacidic residues. Altogether, these findings reveal information encoded within the cytoplasmic proteins required for their unconventional secretion and provide a means to unravel the significance of the cytoplasmic versus the secreted form of mutant SOD1 in the pathology of ALS. We also propose how cells, based on a signal-induced change in cytoplasmic physiology, select a small pool of a subset of cytoplasmic proteins for unconventional secretion.application/pdfeng© 2017 Cruz-Garcia 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.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1083/jcb.201704056DiseaseTraffickinginfo:eu-repo/semantics/openAccess