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. 2024 Mar;79(3):629-642.
doi: 10.1111/all.16004. Epub 2024 Jan 7.

Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8

Wouter Korver  1 , Zachary Benet  1 , Alan Wong  1 , Gian Luca Negri  2 , Katherine Chang  1 , Robert Sanchez  1 , John Leung  1 , Naomi De Freitas  1 , Thuy Luu  1 , Julia Schanin  1 , Bradford A Youngblood  1
Affiliations

Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8

Wouter Korver et al. Allergy. 2024 Mar.

Abstract

Background: Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood.

Methods: Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice.

Results: Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8.

Conclusion: These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

Keywords: KIT; Siglec; interactome; mast cell; proteomics.

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