Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment

• DOI: 10.1172/jci.insight.127751
• Publication Date: 2019-11-26T17:23:57Z
• Authors: Po-Han Chen; Jimin Hu; Jianli Wu; Duc T. Huynh; Timothy J. Smith; Samuel Pan; Brittany J. Bisnett; Alexander B. Smith; Annie Lu; Brett M. Condon; Jen-Tsan Chi; Michael Boyce
• Keywords: Proteostasis

Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause fatal neurodegenerative disease giant axonal neuropathy (GAN), which IF proteins accumulate aggregate axons throughout nervous system, impairing neuronal function viability. Despite this pathophysiological significance, upstream regulation downstream effects normal aberrant remain incompletely understood. Here, we report modified by <italic>O</italic>-linked β-<italic>N</italic>-acetylglucosamine (O-GlcNAc), a prevalent form intracellular glycosylation, nutrient- growth factor–dependent manner. MS analyses revealed 9 candidate sites O-GlcNAcylation, 2 — serine 272 threonine 277 are required for its ability to mediate turnover gigaxonin-deficient cell models created. Taken together, results suggest nutrient-responsive O-GlcNAcylation forms regulatory link between metabolism proteostasis. Our work may have significant implications understanding nongenetic modifiers GAN phenotypes optimization gene therapy disease.