Transmembrane regions of bovine herpesvirus 1-encoded UL49.5 and glycoprotein M regulate complex maturation and ER-Golgi trafficking

Malgorzata Graul, Edyta Kisielnicka, Michal Rychlowski, Marieke Verweij, Kurt Tobler, Mathias Ackermann, Emmanuel J.H.J. Wiertz, Krystyna ieńkowska-Szewczyk, Andrea D. Lipińska

Research output: Contribution to journalArticle

Abstract

Bovine herpesvirus 1 (BoHV-1)-encoded UL49.5 (a homologue of herpesvirus glycoprotein N) can combine different functions, regulated by complex formation with viral glycoprotein M (gM). We aimed to identify the mechanisms governing the immunomodulatory activity of BoHV-1 UL49.5. In this study, we addressed the impact of gM/UL49.5-specific regions on heterodimer formation, folding and trafficking from the endoplasmic reticulum (ER) to the trans-Golgi network (TGN) - events previously found to be responsible for abrogation of the UL49.5-mediated inhibition of the transporter associated with antigen processing (TAP). We first established, using viral mutants, that no other viral protein could efficiently compensate for the chaperone function of UL49.5 within the complex. The cytoplasmic tail of gM, containing putative trafficking signals, was dispensable either for ER retention of gM or for the release of the complex. We constructed cell lines with stable coexpression of BoHV-1 gM with chimeric UL49.5 variants, composed of the BoHV-1 N-terminal domain fused to the transmembrane region (TM) from UL49.5 of varicella-zoster virus or TM and the cytoplasmic tail of influenza virus haemagglutinin. Those membrane-anchored N-terminal domains of UL49.5 were sufficient to form a complex, yet gM/UL49.5 folding and ER-TGN trafficking could be affected by the UL49.5 TM sequence. Finally, we found that leucine substitutions in putative glycine zipper motifs within TM helices of gM resulted in strong reduction of complex formation and decreased ability of gM to interfere with UL49.5-mediated major histocompatibility class I downregulation. These findings highlight the importance of gM/UL49.5 transmembrane domains for the biology of this conserved herpesvirus protein complex.

Original languageEnglish (US)
Article number001224
Pages (from-to)497-510
Number of pages14
JournalJournal of General Virology
Volume100
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

Fingerprint

Bovine Herpesvirus 1
Endoplasmic Reticulum
Glycoproteins
trans-Golgi Network
Herpesviridae
Histocompatibility
Human Herpesvirus 3
Hemagglutinins
Viral Proteins
Orthomyxoviridae
Leucine
Glycine
Down-Regulation
Cell Line

Keywords

  • Alphaherpesviruses
  • Bovine herpesvirus 1
  • Cytoplasmic domain
  • Glycine zipper
  • Transmembrane region
  • UL49.5/glycoprotein M complex

ASJC Scopus subject areas

  • Virology

Cite this

Graul, M., Kisielnicka, E., Rychlowski, M., Verweij, M., Tobler, K., Ackermann, M., ... Lipińska, A. D. (2019). Transmembrane regions of bovine herpesvirus 1-encoded UL49.5 and glycoprotein M regulate complex maturation and ER-Golgi trafficking. Journal of General Virology, 100(3), 497-510. [001224]. https://doi.org/10.1099/jgv.0.001224

Transmembrane regions of bovine herpesvirus 1-encoded UL49.5 and glycoprotein M regulate complex maturation and ER-Golgi trafficking. / Graul, Malgorzata; Kisielnicka, Edyta; Rychlowski, Michal; Verweij, Marieke; Tobler, Kurt; Ackermann, Mathias; Wiertz, Emmanuel J.H.J.; ieńkowska-Szewczyk, Krystyna; Lipińska, Andrea D.

In: Journal of General Virology, Vol. 100, No. 3, 001224, 01.03.2019, p. 497-510.

Research output: Contribution to journalArticle

Graul, M, Kisielnicka, E, Rychlowski, M, Verweij, M, Tobler, K, Ackermann, M, Wiertz, EJHJ, ieńkowska-Szewczyk, K & Lipińska, AD 2019, 'Transmembrane regions of bovine herpesvirus 1-encoded UL49.5 and glycoprotein M regulate complex maturation and ER-Golgi trafficking', Journal of General Virology, vol. 100, no. 3, 001224, pp. 497-510. https://doi.org/10.1099/jgv.0.001224
Graul, Malgorzata ; Kisielnicka, Edyta ; Rychlowski, Michal ; Verweij, Marieke ; Tobler, Kurt ; Ackermann, Mathias ; Wiertz, Emmanuel J.H.J. ; ieńkowska-Szewczyk, Krystyna ; Lipińska, Andrea D. / Transmembrane regions of bovine herpesvirus 1-encoded UL49.5 and glycoprotein M regulate complex maturation and ER-Golgi trafficking. In: Journal of General Virology. 2019 ; Vol. 100, No. 3. pp. 497-510.
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abstract = "Bovine herpesvirus 1 (BoHV-1)-encoded UL49.5 (a homologue of herpesvirus glycoprotein N) can combine different functions, regulated by complex formation with viral glycoprotein M (gM). We aimed to identify the mechanisms governing the immunomodulatory activity of BoHV-1 UL49.5. In this study, we addressed the impact of gM/UL49.5-specific regions on heterodimer formation, folding and trafficking from the endoplasmic reticulum (ER) to the trans-Golgi network (TGN) - events previously found to be responsible for abrogation of the UL49.5-mediated inhibition of the transporter associated with antigen processing (TAP). We first established, using viral mutants, that no other viral protein could efficiently compensate for the chaperone function of UL49.5 within the complex. The cytoplasmic tail of gM, containing putative trafficking signals, was dispensable either for ER retention of gM or for the release of the complex. We constructed cell lines with stable coexpression of BoHV-1 gM with chimeric UL49.5 variants, composed of the BoHV-1 N-terminal domain fused to the transmembrane region (TM) from UL49.5 of varicella-zoster virus or TM and the cytoplasmic tail of influenza virus haemagglutinin. Those membrane-anchored N-terminal domains of UL49.5 were sufficient to form a complex, yet gM/UL49.5 folding and ER-TGN trafficking could be affected by the UL49.5 TM sequence. Finally, we found that leucine substitutions in putative glycine zipper motifs within TM helices of gM resulted in strong reduction of complex formation and decreased ability of gM to interfere with UL49.5-mediated major histocompatibility class I downregulation. These findings highlight the importance of gM/UL49.5 transmembrane domains for the biology of this conserved herpesvirus protein complex.",
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AU - Verweij, Marieke

AU - Tobler, Kurt

AU - Ackermann, Mathias

AU - Wiertz, Emmanuel J.H.J.

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