Trappc11 is required for protein glycosylation in zebrafish and humans

Charles DeRossi, Ana Vacaru, Ruhina Rafiq, Ayca Cinaroglu, Dru Imriea, Shikha Nayar, Anastasia Baryshnikova, Miroslav P. Milev, Daniela Stanga, Dhara Kadakia, Ningguo Gao, Jaime Chu, Hudson H. Freeze, Mark A. Lehrman, Michael Sacher, Kirsten C. Sadler

Research output: Contribution to journalArticle

Abstract

Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in the trappc11 gene, which encodes a component of the transport protein particle (TRAPP) complex. trappc11 mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation in trappc11 mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen in trappc11 mutants and is synthetically lethal with trappc11 mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction in trappc11 mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with the TRAPPC11 mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.

Original languageEnglish (US)
Pages (from-to)1220-1234
Number of pages15
JournalMolecular biology of the cell
Volume27
Issue number8
DOIs
StatePublished - Apr 15 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    DeRossi, C., Vacaru, A., Rafiq, R., Cinaroglu, A., Imriea, D., Nayar, S., Baryshnikova, A., Milev, M. P., Stanga, D., Kadakia, D., Gao, N., Chu, J., Freeze, H. H., Lehrman, M. A., Sacher, M., & Sadler, K. C. (2016). Trappc11 is required for protein glycosylation in zebrafish and humans. Molecular biology of the cell, 27(8), 1220-1234. https://doi.org/10.1091/mbc.E15-08-0557