Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response

Weinhofer, I. et al. (2022) Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response. Communications Biology, 5, 944. (doi: 10.1038/s42003-022-03867-y) (PMID:36085307) (PMCID:PMC9462615)

Abstract

Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection. Here, we used Epstein-Barr virus (EBV) infection of human B cells to elucidate how herpesviruses target VLCFA metabolism. Gene expression profiling revealed that, despite a general induction of peroxisome-related genes, EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation. The mechanism underlying ABCD1 and ABCD2 repression involved RNA interference by the EBV-induced microRNAs miR-9-5p and miR-155, respectively, causing significantly increased VLCFA levels. Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes, and, upon lytic reactivation, reduced virus production in control but not ABCD1-deficient cells. Finally, also other herpesviruses and coronaviruses target ABCD1 expression. Because viral infection might trigger neuroinflammation in X-linked adrenoleukodystrophy (X-ALD, inherited ABCD1 deficiency), we explored a possible link between EBV infection and cerebral X-ALD. However, neither immunohistochemistry of post-mortem brains nor analysis of EBV seropositivity in 35 X-ALD children supported involvement of EBV in the onset of neuroinflammation. Collectively, our findings indicate a previously unrecognized, pivotal role of ABCD1 in viral infection and host defence, prompting consideration of other viral triggers in cerebral X-ALD.

• Item Type: Articles
• Additional Information: This work was supported by the Austrian Science Fund KLI 837-B to I.W. and DOC 33-B27 to J.B.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hesse, Ms Sarah
• Authors: Weinhofer, I., Buda, A., Kunze, M., Palfi, Z., Traunfellner, M., Hesse, S., Villoria-Gonzalez, A., Hofmann, J., Hametner, S., Regelsberger, G., Moser, A. B., Eichler, F., Kemp, S., Bauer, J., Kühl, J.-S., Forss-Petter, S., and Berger, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Communications Biology
• Publisher: Nature Research
• ISSN: 2399-3642
• ISSN (Online): 2399-3642
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Communications Biology 5: 944
• Publisher Policy: Reproduced under a Creative Commons License