Surface proteins, ERAD and antigenic variation in Trypanosoma brucei.
Variant surface glycoprotein (VSG) is central to antigenic variation in African trypanosomes. Although much prior work documents that VSG is efficiently synthesized and exported to the cell surface, it was recently claimed that 2-3 fold more is synthesized than required, the excess being eliminated by ER-Associated Degradation (ERAD) (Field et al., ). We now reinvestigate VSG turnover and find no evidence for rapid degradation, consistent with a model whereby VSG synthesis is precisely regulated to match requirements for a functional surface coat on each daughter cell. However, using a mutated version of the ESAG7 subunit of the transferrin receptor (E7:Ty) we confirm functional ERAD in trypanosomes. E7:Ty fails to assemble into transferrin receptors and accumulates in the ER, consistent with retention of misfolded protein, and its turnover is selectively rescued by the proteasomal inhibitor MG132. We also show that ER accumulation of E7:Ty does not induce an unfolded protein response. These data, along with the presence of ERAD orthologues in the Trypanosoma brucei genome, confirm ERAD in trypanosomes. We discuss scenarios in which ERAD could be critical to bloodstream parasites, and how these may have contributed to the evolution of antigenic variation in trypanosomes.
Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, NY, 14214, USA.
Calvin
C
Tiengwe
Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, 55455, USA.
Katherine A
KA
Muratore
Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, NY, 14214, USA. jdbangs@buffalo.edu.
James D
JD
Bangs
D000953:Antigens, Protozoan / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D017510:Protein Folding; D055550:Protein Stability; D059748:Proteolysis; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000378:metabolism*
D000953:Antigens, Protozoan; D014643:Variant Surface Glycoproteins, Trypanosoma