The Francis Crick Institute
MIZ1 manuscript for deposition.pdf (23.23 MB)

Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TMBIM4 safeguards IgG1+ GC B cell-positive selection.

Download (23.23 MB)
journal contribution
posted on 2024-04-22, 08:59 authored by Lingling Zhang, Amparo Toboso-Navasa, Arief Gunawan, Abdouramane Camara, Rinako Nakagawa, Katja Finsterbusch, Probir Chakravarty, Rebecca Newman, Yang Zhang, Martin Eilers, Andreas Wack, Pavel Tolar, Kai-Michael Toellner, Dinis Pedro Calado
The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG+ B cells over IgM+ B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1+ GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1+ GC B cell survival during positive selection, whereas IgM+ GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)-mediated calcium (Ca2+) mobilization downstream of B cell receptor (BCR) signaling in IgG1+ B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1+ GC cell death caused by excessive Ca2+ accumulation. This study uncovers a unique Ig isotype-specific dependency on a hitherto unidentified mechanism in GC-positive selection.


Crick (Grant ID: CC2085, Grant title: Wack CC2085) Crick (Grant ID: CC2006, Grant title: Tolar CC2006) Crick (Grant ID: CC2078, Grant title: Calado CC2078) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics)