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Molecular and Cellular Biology, April 2006, p. 2697-2715, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2697-2715.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cell-Specific Metabolism and Pathogenesis of Transmembrane Prion Protein

Yaping Gu, Xiu Luo, Subhabrata Basu, Hisashi Fujioka, and Neena Singh*

Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106

Received 18 August 2005/ Returned for modification 6 October 2005/ Accepted 5 January 2006

The C-transmembrane form of prion protein (CtmPrP) has been implicated in prion disease pathogenesis, but the factors underlying its biogenesis and cyotoxic potential remain unclear. Here we show that CtmPrP 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 CtmPrP 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 CtmPrP regardless of the charge conferred to the N region. Subsequent processing and transport of CtmPrP 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 CtmPrP upregulation in naturally occurring prion disorders remains elusive, these data highlight the underlying mechanisms of CtmPrP biogenesis and neurotoxicity and reinforce the idea that CtmPrP may serve as the proximate cause of neuronal death in certain prion disorders.

* Corresponding author. Mailing address: Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106. Phone: (216) 368-2617. Fax: (216) 368-2546. E-mail: neena.singh{at}case.edu.

Molecular and Cellular Biology, April 2006, p. 2697-2715, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2697-2715.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ott, C. M., Akhavan, A., Lingappa, V. R. (2007). Specific Features of the Prion Protein Transmembrane Domain Regulate Nascent Chain Orientation. J. Biol. Chem. 282: 11163-11171 [Abstract] [Full Text]  


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