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Journal of Virology, May 2004, p. 4776-4782, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4776-4782.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Scrapie Protein Degradation by Cysteine Proteases in CD11c+ Dendritic Cells and GT1-1 Neuronal Cells

Katarina M. Luhr,1* Elin K. Nordström,1 Peter Löw,1 Hans-Gustaf Ljunggren,2 Albert Taraboulos,3 and Krister Kristensson1

Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm,1 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Stockholm, Sweden,2 Department of Molecular Biology, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel3

Received 21 July 2003/ Accepted 14 November 2003

Dendritic cells (DC) of the CD11c+ myeloid phenotype have been implicated in the spread of scrapie in the host. Previously, we have shown that CD11c+ DC can cause a rapid degradation of proteinase K-resistant prion proteins (PrPSc) in vitro, indicating a possible role of these cells in the clearance of PrPSc. To determine the mechanisms of PrPSc degradation, CD11c+ DC that had been exposed to PrPSc derived from a neuronal cell line (GT1-1) infected with scrapie (ScGT1-1) were treated with a battery of protease inhibitors. Following treatment with the cysteine protease inhibitors (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c), its ethyl ester (E-64d), and leupeptin, the degradation of PrPSc was inhibited, while inhibitors of serine and aspartic and metalloproteases (aprotinin, pepstatin, and phosphoramidon) had no effect. An endogenous degradation of PrPSc in ScGT1-1 cells was revealed by inhibiting the expression of cellular PrP (PrPC) by RNA interference, and this degradation could also be inhibited by the cysteine protease inhibitors. Our data show that PrPSc is proteolytically cleaved preferentially by cysteine proteases in both CD11c+ DC and ScGT1-1 cells and that the degradation of PrPSc by proteases is different from that of PrPC. Interference by protease inhibitors with DC-induced processing of PrPSc has the potential to modify prion spread, clearance, and immunization in a host.

* Corresponding author. Mailing address: Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Phone: 46-8-728 78 27. Fax: 46-8-325 325. E-mail: katarina.luhr{at}neuro.ki.se.

Journal of Virology, May 2004, p. 4776-4782, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4776-4782.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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