The Proteomic Landscape of Cysteine Oxidation That Underpins Retinoic Acid-Induced Neuronal Differentiation

The initial phases of neuronal differentiation
are key to neuronal
function. A particularly informative model to study these initial
phases are retinoic acid-stimulated SH-SY5Y cells. Although these
progressions are associated with redox-sensitive processes, it is
largely undefined how the cellular proteome underpins redox dynamics
and the management of reactive oxygen species. Here, we map the global
cysteine-based redox landscape of SH-SY5Y cells using quantitative
redox proteomics. We find evidence that redox alterations occurred
early in differentiation and affect the expression of neuronal marker
proteins and the extension of neurites. The spatiotemporal analysis
of reactive oxygen species suggests a NOX2-dependent peak in cytoplasmic
superoxide anions/hydrogen peroxide generation 2 h after retinoic
acid stimulation. At the same time point, 241 out of 275 proteins
with an altered cysteine redox state are reversibly oxidized in response
to retinoic acid. Our analyses pinpoint redox alterations of proteins
involved in the retinoic acid homeostasis and cytoskeletal dynamics.