|ZFIN ID: ZDB-PUB-160226-3|
trappc11 is required for protein glycosylation in zebrafish and humans
DeRossi, C., Vacaru, A., Rafiq, R., Cinaroglu, A., Imrie, 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.
|Source:||Molecular biology of the cell 27(8): 1220-34 (Journal)|
|Registered Authors:||Chu, Jaime, Cinaroglu, Ayca, DeRossi, Charles, Imrie, Dru, Nayar, Shikha, Rafiq, Ruhina, Sadler Edepli, Kirsten C., Vacaru, Ana|
|PubMed:||26912795 Full text @ Mol. Biol. Cell|
DeRossi, C., Vacaru, A., Rafiq, R., Cinaroglu, A., Imrie, 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):1220-34.
ABSTRACTActivation of the unfolded protein response (UPR) can be either adaptive or pathological. We termed the pathological UPR that causes fatty liver disease a "stressed UPR". Here, we investigated the mechanism of stressed UPR activation in zebrafish bearing mutation in the trappc11 gene that encodes a component of the transport protein particle (TRAPP) complex. trappc11 mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. Additionally, we uncovered a defect in protein glycosylation in trappc11 mutants which was associated with reduced levels of lipid linked oligosaccharides (LLO) and compensatory upregulation of genes in the terpenoid biosynthetic pathway which produces the LLO anchor, dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopied the stressed UPR seen in trappc11 mutants and was synthetically lethal with trappc11 mutation. We propose reduced LLO levels causing hypoglycosylation is a mechanism of stressed UPR induction in trappc11 mutants. Importantly, in human cells, depletion of TRAPPC11, but not other TRAPP components, caused protein hypoglycosylation, and lipid droplets accumulated in fibroblasts from patients with 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.