Cell-specific metabolism and pathogenesis of transmembrane prion protein.
The C-transmembrane form of prion protein ((Ctm)PrP) has been implicated in prion disease pathogenesis, but the factors underlying its biogenesis and cyotoxic potential remain unclear. Here we show that (Ctm)PrP interferes with cytokinesis in cell lines where it is transported to the plasma membrane. These cells fail to separate following cell division, assume a variety of shapes and sizes, and contain multiple nuclei, some of which are pyknotic. Furthermore, the synthesis and transport of (Ctm)PrP to the plasma membrane are modulated through a complex interaction between cis- and trans-acting factors and the endoplasmic reticulum translocation machinery. Thus, insertion of eight amino acids before or within the N region of the N signal peptide (N-SP) of PrP results in the exclusive synthesis of (Ctm)PrP regardless of the charge conferred to the N region. Subsequent processing and transport of (Ctm)PrP are modulated by specific amino acids in the N region of the N-SP and by the cell line of expression. Although the trigger for (Ctm)PrP upregulation in naturally occurring prion disorders remains elusive, these data highlight the underlying mechanisms of (Ctm)PrP biogenesis and neurotoxicity and reinforce the idea that (Ctm)PrP may serve as the proximate cause of neuronal death in certain prion disorders.
Gu
Yaping
Y
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA.
Luo
Xiu
X
Basu
Subhabrata
S
Fujioka
Hisashi
H
Singh
Neena
N
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D048749:Cytokinesis; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D011328:Prions / Q000737:chemistry / Q000378:metabolism* / Q000472:pathogenicity* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism
C110396:(ctm)PrP; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011328:Prions; D011994:Recombinant Proteins