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Viruses 2012, 4(11), 2471-2484; doi:10.3390/v4112471
Article

Niemann-Pick C1 (NPC1)/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor

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Received: 22 August 2012; in revised form: 10 October 2012 / Accepted: 18 October 2012 / Published: 25 October 2012
(This article belongs to the Special Issue Advances in Filovirus Research 2012)
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Abstract: We recently demonstrated that Niemann-Pick C1 (NPC1), a ubiquitous 13-pass cellular membrane protein involved in lysosomal cholesterol transport, is a critical entry receptor for filoviruses. Here we show that Niemann-Pick C1-like1 (NPC1L1), an NPC1 paralog and hepatitis C virus entry factor, lacks filovirus receptor activity. We exploited the structural similarity between NPC1 and NPC1L1 to construct and analyze a panel of chimeras in which NPC1L1 sequences were replaced with cognate sequences from NPC1. Only one chimera, NPC1L1 containing the second luminal domain (C) of NPC1 in place of its own, bound to the viral glycoprotein, GP. This engineered protein mediated authentic filovirus infection nearly as well as wild-type NPC1, and more efficiently than did a minimal NPC1 domain C-based receptor recently described by us. A reciprocal chimera, NPC1 containing NPC1L1’s domain C, was completely inactive. Remarkably, an intra-domain NPC1L1-NPC1 chimera bearing only a ~130-amino acid N–terminal region of NPC1 domain C could confer substantial viral receptor activity on NPC1L1. Taken together, these findings account for the failure of NPC1L1 to serve as a filovirus receptor, highlight the central role of the luminal domain C of NPC1 in filovirus entry, and reveal the direct involvement of N–terminal domain C sequences in NPC1’s function as a filovirus receptor.
Keywords: Ebola virus; Marburg virus; filovirus; viral entry; Niemann-Pick C1; NPC1; Niemann-Pick C1-like1; NPC1L1; host factor; viral receptor Ebola virus; Marburg virus; filovirus; viral entry; Niemann-Pick C1; NPC1; Niemann-Pick C1-like1; NPC1L1; host factor; viral receptor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Krishnan, A.; Miller, E.H.; Herbert, A.S.; Ng, M.; Ndungo, E.; Whelan, S.P.; Dye, J.M.; Chandran, K. Niemann-Pick C1 (NPC1)/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor. Viruses 2012, 4, 2471-2484.

AMA Style

Krishnan A, Miller EH, Herbert AS, Ng M, Ndungo E, Whelan SP, Dye JM, Chandran K. Niemann-Pick C1 (NPC1)/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor. Viruses. 2012; 4(11):2471-2484.

Chicago/Turabian Style

Krishnan, Anuja; Miller, Emily H.; Herbert, Andrew S.; Ng, Melinda; Ndungo, Esther; Whelan, Sean P.; Dye, John M.; Chandran, Kartik. 2012. "Niemann-Pick C1 (NPC1)/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor." Viruses 4, no. 11: 2471-2484.



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