A Spatiotemporal Map of Co-Receptor Signaling Networks Underlying B Cell Activation

• Published in: bioRxiv
• Main Authors: Susa, Katherine J, Bradshaw, Gary A, Eisert, Robyn J, Schilling, Charlotte M, Kalocsay, Marian, Blacklow, Stephen C, Kruse, Andrew C
• Format: Journal Article
• Language: English
• Published: United States 21.03.2023
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.03.17.533227

The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. This process underlies nearly every aspect of proper B cell function. Here, we take advantage of peroxidase-catalyzed proximity labeling combined with quantitative mass spectrometry to track B cell co-receptor signaling dynamics from 10 seconds to 2 hours after BCR stimulation. This approach enables tracking of 2,814 proximity-labeled proteins and 1,394 quantified phosphosites and provides an unbiased and quantitative molecular map of proteins recruited to the vicinity of CD19, the key signaling subunit of the co-receptor complex. We detail the recruitment kinetics of essential signaling effectors to CD19 following activation, and then identify new mediators of B cell activation. In particular, we show that the glutamate transporter SLC1A1 is responsible for mediating rapid metabolic reprogramming immediately downstream of BCR stimulation and for maintaining redox homeostasis during B cell activation. This study provides a comprehensive map of the BCR signaling pathway and a rich resource for uncovering the complex signaling networks that regulate B cell activation.