Biology subjects

Mattila, P. K.

Publications and source records attributed to Mattila, P. K..

3 recordsLinked to original sources

bioRxiv2024

Distal super-enhancer drives aberrant CXCL13 in Cancer cells driving growth and p53 dysregulation via CXCR5-CXCL13 axis

The CXCL13 chemokine plays a crucial role in guiding B cell migration to the light zones (LZs) during the germinal center (GC) reaction. While CXCL13 expression is absent in most cell types, aberrant amplification of the CXCR5-CXCL13 signaling is observed in various cancers, including germinal center-derived B-lymphomas (GCDBL), colorectal adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC). However, the molecular mechanisms underlying abnormal CXCL13 transcription in cancer cells and its functional consequences remain elusive. We identify DNA-CpG methylation binding protein 1 (MBD1) as a suppressor of CXCL13 expression. Chromosomal conformation capture (3C) analysis reveals a distal super-enhancer located near CCNG2 that interacts with the CXCL13 promoter in GCDBL, suggesting that enhancer-hijacking drives the aberrant expression. Our functional validation demonstrates that CXCR5-CXCL13 signaling suppresses p53 and its target genes in GCDBLs, COAD, and LIHC. Notably, CXCL13 in the GCDBL cell line Raji disrupts CXCR5-mediated migration, a mechanism essential for (light zone) LZ-entry and affinity maturation of GC B cells. These findings highlight the dual role of the CXCR5-CXCL13 axis in immune response and cancer proliferation. Key PointsO_LISuper-enhancer near CCNG2 region interacts with CXCL13-TSS driving CXCL13 in cancers. C_LIO_LIAberrant CXCL13 prevents CXCR5-mediated migration of B-lymphomas and promotes growth and p53 dysregulation in CXCR5+ cells C_LIO_LICXCR5-CXCL13 axis impairs p53 target gene expression and promotes tumor growth C_LI O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/609994v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@abf94corg.highwire.dtl.DTLVardef@7bfd55org.highwire.dtl.DTLVardef@351645org.highwire.dtl.DTLVardef@1493e62_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAberrant CXCL13 expression in hematological and solid cancers C_LIO_LIChemotherapeutic treatment of cancer cells promotes CXCL13 and CXCR5 expression C_LIO_LIDistal super-enhancer on CCNG2 interacts with CXCL13 promoter C_LIO_LICXCL13 expression in B-lymphomas prevents CXCR5-dependent migration C_LIO_LICXCR5-CXCL13 axis encounters p53 function in hematological and solid cancer cells C_LI

cancer biology↗

bioRxiv2023

Spatiotemporal control of microtubule acetylation by mechanical cues regulates lysosome dynamics at the immune synapse of B cells to promote antigen presentation

The capacity of B cells to extract immobilized antigens through the formation of an immune synapse can be tuned by the physical characteristics of the surface where antigens are encountered. However, the underlying mechanisms that couple mechanosensing by B cells to antigen extraction and processing remain poorly understood. We show that B cells activated by antigens associated with stiffer substrates exhibit enhanced spreading responses and higher tubulin acetylation at the center of the immune synapse, where less motile lysosomes preferentially localize. This process is coupled to the translocation of the microtubule acetylase, ATAT1 to the cytoplasm of B cells, which occurs as a mechano-response during BCR stimulation. Accordingly, B cells silenced for ATAT1 are unable to stabilize lysosomes at the synaptic interface and display a lower capacity to extract and present immobilized antigens to T cells. Overall, these findings highlight how BCR-dependent mechano-responses trigger microtubule network modifications to precisely orchestrate lysosome positioning to promote antigen extraction and presentation in B cells.

cell biology↗

bioRxiv2020

APEX2 proximity biotinylation reveals protein dynamics triggered by B cell receptor activation

Successful B cell activation, critical for high-affinity antibody production, is controlled by the B cell antigen receptor (BCR). However, we still lack a comprehensive protein-level view of the very dynamic multi-branched cellular events triggered by antigen binding. Here, we employed APEX2 proximity biotinylation to study antigen-induced changes, 5-15 min after receptor activation, at the vicinity of the plasma membrane lipid rafts, wherein BCR enriches upon activation. The data reveals dynamics of signaling proteins, as well as various players linked to the subsequent processes, such as actin cytoskeleton remodelling and endocytosis. Interestingly, our differential expression analysis identified dynamic responses in various proteins previously not linked to early B cell activation. We demonstrate active SUMOylation at the sites of BCR activation in various conditions and report its functional role in BCR signaling through Akt and MAPK axes.

immunology↗