trappc11 is required for protein glycosylation in zebrafish and humans

Molecular Biology of the Cell
Charles DeRossiKirsten C Sadler

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 thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants 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 intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. 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 theTRAPPC11mutation. These data po...Continue Reading

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Citations

Nov 20, 2016·Human Mutation·Leslie MatalongaMarisa Girós
Dec 28, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Elizabeth A O'HareNorann A Zaghloul
Aug 23, 2017·Journal of Clinical Neuromuscular Disease·Dominic B FeeErika Pyzik
Jul 6, 2019·Scientific Reports·Nicholas J BarrowsMariano A Garcia-Blanco
Aug 15, 2018·Case Reports in Genetics·Xike WangYuchuan Wang
Sep 5, 2018·Frontiers in Cell and Developmental Biology·Liqing ZangWenbiao Chen
Sep 26, 2020·Biomolecules·Maximilian Breuer, Shunmoogum A Patten
Nov 4, 2017·Current Pathobiology Reports·Duc-Hung PhamChunyue Yin
Jun 14, 2020·Protein and Peptide Letters·Gabriele PogliaghiMarco Bonomi
Oct 15, 2021·Neuropathology and Applied Neurobiology·Pinki MunotFrancesco Muntoni

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Methods Mentioned

BETA
protein folding
glycosylation
PCR
transgenic
Confocal microscopy
electrophoresis
Confocal
transfection
nucleotide exchange
protein

Software Mentioned

NIS
ImageJ
GraphPad
SAFE
Imaris
Prism
Elements C

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