Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties

Alessandro Vacchini, Anneleen Mortier, Paul Proost, Massimo Locati, Mieke Metzemaekers, Elena Monica Borroni

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

CXCL8 or interleukin (IL)-8 directs neutrophil migration and activation through interaction with CXCR1 and CXCR2 that belong to the family of G protein-coupled receptors (GPCRs). Naturally occurring posttranslational modifications of the NH 2 -terminal region of CXCL8 affect its biological activities, but the underlying molecular mechanisms are only partially understood. Here, we studied the implications of site-specific citrullination and truncation for the signaling potency of CXCL8. Native CXCL8(1-77), citrullinated [Cit5]CXCL8(1-77) and the major natural isoform CXCL8(6-77) were chemically synthesized and tested in internalization assays using human neutrophils. Citrullinated and truncated isoforms showed a moderately enhanced capacity to induce internalization of CXCR1 and CXCR2. Moreover, CXCL8-mediated activation of Gα i -dependent signaling through CXCR1 and CXCR2 was increased upon modification to [Cit5]CXCL8(1-77) or CXCL8(6-77). All CXCL8 variants promoted recruitment of β-arrestins 1 and 2 to CXCR1 and CXCR2. Compared to CXCL8(1-77), CXCL8(6-77) showed an enhanced potency to recruit β-arrestin 2 to both receptors, while for [Cit5]CXCL8(1-77) only the capacity to induce β-arrestin 2 recruitment to CXCR2 was increased. Both modifications had no biasing effect, i.e., did not alter the preference of CXCL8 to activate either Gα i -protein or β-arrestin-dependent signaling through its receptors. Our results support the concept that specific chemokine activities are fine-tuned by posttranslational modifications.

Original languageEnglish
Article number3768
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume19
Issue number12
DOIs
Publication statusPublished - 27 Nov 2018

Keywords

  • Endocytosis
  • Humans
  • Interleukin-8/chemistry
  • Neutrophils/immunology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Protein Transport
  • Receptors, Interleukin-8A/metabolism
  • Receptors, Interleukin-8B/metabolism
  • Signal Transduction
  • beta-Arrestins/metabolism

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