ERAD and disposal of misfolded GPI-anchored proteins in Trypanosoma brucei

Tue10  Apr10:15am(15 mins)
Where:
Stream 1 - Edward Llwyd 0.26 Biology Main
Dr Calvin Tiengwe

Authors

C Tiengwe1; J D Bangs1
1 University at Buffalo (SUNY), United States

Discussion

Misfolded secretory proteins are generally retrotranslocated from the ER and degraded in the proteasome by ER-associated degradation (ERAD). However, in yeasts and mammals, where glycosylphosphatidylinositol (GPI) anchors are forward trafficking signals, misfolded GPI-anchored proteins are preferentially delivered to the vacuole/lysosome for disposal. Using the phylogenetically ancient parasite Trypanosoma brucei as a model system, we test the universality of this process with a misfolded subunit of the transferrin receptor (TfR). TfR is a heterodimer of GPI-anchored ESAG6 and non-GPI ESAG7. When expressed with ESAG7, misfolded ESAG6 assembles into heterodimers, but are non-functional for Tf binding. When expressed alone, misfolded ESAG6 is N-glycosylated and GPI-anchored, but accumulates in the ER as monomers/aggregates. Treatment with MG132, a proteasome inhibitor, generates a protected polypeptide that is full length, soluble, cytosolic, and de-N-glycosylated. This protected polypeptide is non-reactive with anti-CRD antibody, a GPI-specific reagent, indicating that GPI destruction precedes delivery to the proteasome. The trypanosome GPI anchor is a forward trafficking signal, thus the dynamic tension between ERAD and ER exit favors degradation by ERAD. These results differ markedly from the standard eukaryotic model systems and may indicate an evolutionary advantage related to pathogenesis.
Schedule

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