Endoplasmic reticulum-associated degradation and disposal of misfolded GPI-anchored proteins in Trypanosoma brucei. 2018

Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214.

Misfolded secretory proteins are retained by endoplasmic reticulum quality control (ERQC) and degraded in the proteasome by ER-associated degradation (ERAD). However, in yeast and mammals, misfolded glycosylphosphatidylinositol (GPI)-anchored proteins are preferentially degraded in the vacuole/lysosome. We investigate this process in the divergent eukaryotic pathogen Trypanosoma brucei using a misfolded GPI-anchored subunit (HA:E6) of the trypanosome transferrin receptor. HA:E6 is N-glycosylated and GPI-anchored and accumulates in the ER as aggregates. Treatment with MG132, a proteasome inhibitor, generates a smaller protected polypeptide (HA:E6*), consistent with turnover in the proteasome. HA:E6* partitions between membrane and cytosol fractions, and both pools are proteinase K-sensitive, indicating cytosolic disposition of membrane-associated HA:E6*. HA:E6* is de-N-glycosylated and has a full GPI-glycan structure from which dimyristoylglycerol has been removed, indicating that complete GPI removal is not a prerequisite for proteasomal degradation. However, HA:E6* is apparently not ubiquitin-modified. The trypanosome GPI anchor is a forward trafficking signal; thus the dynamic tension between ERQC 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.

UI MeSH Term Description Entries
D007976 Leupeptins A group of acylated oligopeptides produced by Actinomycetes that function as protease inhibitors. They have been known to inhibit to varying degrees trypsin, plasmin, KALLIKREINS, papain and the cathepsins.
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D011990 Receptors, Transferrin Membrane glycoproteins found in high concentrations on iron-utilizing cells. They specifically bind iron-bearing transferrin, are endocytosed with its ligand and then returned to the cell surface where transferrin without its iron is released. Transferrin Receptors,Transferrin Receptor,Receptor, Transferrin
D014346 Trypanosoma brucei brucei A hemoflagellate subspecies of parasitic protozoa that causes nagana in domestic and game animals in Africa. It apparently does not infect humans. It is transmitted by bites of tsetse flies (Glossina). Trypanosoma brucei,Trypanosoma brucei bruceus,Trypanosoma bruceus,brucei brucei, Trypanosoma,brucei, Trypanosoma brucei,bruceus, Trypanosoma,bruceus, Trypanosoma brucei
D015800 Protozoan Proteins Proteins found in any species of protozoan. Proteins, Protozoan
D017261 Glycosylphosphatidylinositols Compounds containing carbohydrate or glycosyl groups linked to phosphatidylinositols. They anchor GPI-LINKED PROTEINS or polysaccharides to cell membranes. GPI Membrane Anchor,GPI Membrane Anchors,Glycosyl-Phosphatidylinositol Membrane Protein Anchor,Glycosylated Phosphatidylinositol,Glycosylphosphatidylinositol Anchor,Glycosylphosphatidylinositol Anchors,Phosphatidylinositol Glycan,Gly-PtdIns,Glycoinositol Phospholipid Membrane Anchor,Glycosyl-Phosphatidylinositol,Glycosyl-Phosphatidylinositol Membrane Protein Anchors,Glycosylated Phosphatidylinositols,Glycosylphosphatidylinositol,Glycosylphosphatidylinositol Linkage,PI-Glycan,Anchor, GPI Membrane,Anchor, Glycosylphosphatidylinositol,Anchors, GPI Membrane,Anchors, Glycosylphosphatidylinositol,Glycan, Phosphatidylinositol,Glycosyl Phosphatidylinositol,Glycosyl Phosphatidylinositol Membrane Protein Anchor,Glycosyl Phosphatidylinositol Membrane Protein Anchors,Linkage, Glycosylphosphatidylinositol,Membrane Anchor, GPI,Membrane Anchors, GPI,PI Glycan,Phosphatidylinositol, Glycosylated,Phosphatidylinositols, Glycosylated
D017510 Protein Folding Processes involved in the formation of TERTIARY PROTEIN STRUCTURE. Protein Folding, Globular,Folding, Globular Protein,Folding, Protein,Foldings, Globular Protein,Foldings, Protein,Globular Protein Folding,Globular Protein Foldings,Protein Foldings,Protein Foldings, Globular
D059748 Proteolysis Cleavage of proteins into smaller peptides or amino acids either by PROTEASES or non-enzymatically (e.g., Hydrolysis). It does not include Protein Processing, Post-Translational. Protein Degradation,Protein Digestion,Degradation, Protein,Degradations, Protein,Digestion, Protein,Digestions, Protein,Protein Degradations,Protein Digestions,Proteolyses
D060746 Endoplasmic Reticulum-Associated Degradation A degradation process whereby incorrectly folded proteins are selectively transported out of the ENDOPLASMIC RETICULUM and into the CYTOSOL. The misfolded proteins are subsequently ubiquitinated and degraded by the PROTEASOME. ERAD Pathway,Degradation, Endoplasmic Reticulum-Associated,ERAD Pathways,Endoplasmic Reticulum Associated Degradation,Pathway, ERAD,Pathways, ERAD,Reticulum-Associated Degradation, Endoplasmic
D017930 Genes, Reporter Genes whose expression is easily detectable and therefore used to study promoter activity at many positions in a target genome. In recombinant DNA technology, these genes may be attached to a promoter region of interest. Reporter Genes,Gene, Reporter,Reporter Gene

Related Publications

Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
July 2019, International journal of molecular sciences,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
February 1994, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
September 2021, Current biology : CB,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
May 2010, Journal of cell science,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
June 1999, Laboratory investigation; a journal of technical methods and pathology,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
August 2004, Molecular microbiology,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
December 2004, Current opinion in cell biology,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
September 2021, Cell reports,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
April 2000, Nature structural biology,
Calvin Tiengwe, and Carolina M Koeller, and James D Bangs
March 2013, The FEBS journal,
Copied contents to your clipboard!