A diacidic motif determines unconventional secretion of wild-type and ALS-linked mutant SOD1

Cruz-Garcia, David; Brouwers, Nathalie; Duran, Juan M.; Mora, Gabriel; Curwin, Amy; Malhotra, Vivek

doi:http://dx.doi.org/10.1083/jcb.201704056

A diacidic motif determines unconventional secretion of wild-type and ALS-linked mutant SOD1

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Cruz-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.201704056

Abstract

The 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.