Biology subjects

Franke, S.

Publications and source records attributed to Franke, S..

4 recordsLinked to original sources

bioRxiv2024

Cellular and molecular events organizing the assembly of tertiary lymphoid structures in glioblastoma

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates associated with improved prognosis in numerous tumors. To date, their prognostic value in central nervous system cancers and the events underlying their formation remain unclear. Here, we find that TLS correlate with improved survival in glioblastoma patients. Furthermore, combining spatial transcriptomics of human tissues with longitudinal studies in murine glioma, we establish that the assembly of T cell-rich clusters is a prerequisite for the development of canonical TLS, and show that CD4 T cells play a central role in this process. Indeed, we provide evidence that IL7R+CCR7+ Th1 lymphocytes with lymphoid tissue-inducing potential are recruited to TLS nucleation sites, where they can initiate TLS assembly by expressing lymphotoxin {beta}. Our work defines TLS as a potential prognostic factor in glioblastoma and identifies cellular and molecular mechanisms of TLS formation. These findings have broader implications for the development of TLS-inducing therapies for cancer. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/601824v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@78be05org.highwire.dtl.DTLVardef@1037706org.highwire.dtl.DTLVardef@7b64e1org.highwire.dtl.DTLVardef@11bfd5c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Impaired transitioning of the FXR ligand binding domain to an active state underlies a PFIC5 phenotype

Nuclear receptor farnesoid X receptor (FXR) acts as a key regulator of bile acid pool homeostasis and metabolism. Within the enterohepatic circulation, reabsorbed bile acids act as FXR agonists, which transcriptionally controls the synthesis and transport of bile acids. Binding occurs in the ligand binding domain (LBD), favoring a conformational change to the active state in which helix 12 interacts with the LBD to form an interaction surface for nuclear co-activators. The homozygous missense variant T296I, identified in a PFIC patient, is located close to the critical helix 12 interaction. Here, we identified reduced transcriptional activity of the variant protein on the downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, within the patients liver, and in iPSC-derived hepatic organoids. BSEP-dependent Tauro-DBD transport was impaired in T296I patient-derived organoids, but could be rescued via lipid nanoparticle-mediated FXR WT mRNA delivery, indicating the variant is responsible for the identified reduced BSEP expression. Using molecular dynamics simulations, we observed a reduced transitioning from the inactive to the active state for the T296I variant, indicating a molecular mechanism underlying the reduced activity. To our knowledge, this is the first study to describe the conformational change from an inactive to an active state of the FXR LBD. This might be useful for new therapeutic approaches targeting the activation of FXR.

physiology↗

bioRxiv2019

Interspecies metabolite transfer in a co-culture of Dehalococcoides and Sulfurospirillum leads to rapid and complete tetrachloroethene dechlorination

Microbial communities involving dehalogenating bacteria assist in bioremediation of areas contaminated with halocarbons. To understand molecular interactions between dehalogenating bacteria, we co-cultured Sulfurospirillum multivorans, dechlorinating tetrachloroethene (PCE) to cis-1,2-dichloroethene (cDCE), and Dehalococcoides mccartyi strains BTF08 or 195, dehalogenating PCE to ethene. The co-cultures were cultivated with lactate as electron donor. In this co-culture, the bacterial cells formed aggregates and D. mccartyi established an unusual, barrel-like morphology. An extracellular matrix surrounding bacterial cells in the aggregates enhanced cell-to-cell contact. PCE was dehalogenated to ethene at least three times faster in the co-culture. The dehalogenation was carried out via PceA of S. multivorans, and PteA (a recently described PCE dehalogenase) and VcrA of D. mccartyi BTF08, as supported by protein abundance. The co-culture was not dependent on exogenous hydrogen and acetate, suggesting a syntrophic relationship in which the obligate hydrogen consumer D. mccartyi consumes hydrogen and acetate produced by S. multivorans. The cobamide cofactor of the reductive dehalogenase - mandatory for D. mccartyi - was also produced by S. multivorans. D. mccartyi strain 195 dechlorinated cDCE in the presence of norpseudo-B12 produced by S. multivorans, but D. mccartyi strain BTF08 depended on an exogenous lower cobamide ligand. This observation is important for bioremediation, since cofactor supply in the environment might be a limiting factor for PCE dehalogenation to ethene, described for D. mccartyi exclusively. The findings from this co-culture give new insights into aggregate formation and the physiology of D. mccartyi within a bacterial community.

microbiology↗

bioRxiv2017

3’UTR Remodelling of Axonal Transcripts in Sympathetic Neurons

The 3 untranslated regions (3UTRs) of messenger RNAs (mRNA) are non-coding sequences that regulate several aspects of mRNA metabolism, including intracellular localisation and translation. Here, we show that in sympathetic neuron axons, the 3UTRs of many transcripts undergo cleavage, generating both translatable isoforms expressing a shorter 3UTR, and 3UTR fragments. 3end RNA sequencing indicated that 3UTR cleavage is a potentially widespread event in axons, which is mediated by a protein complex containing the endonuclease Ago2 and the RNA binding protein HuD. Analysis of the Inositol monophosphatase 1 (Impa1) mRNA revealed that a stem loop structure within the 3UTR is necessary for Ago2 cleavage. Thus, remodeling of the 3UTR provides an alternative mechanism that simultaneously regulates local protein synthesis and generates a new class of 3UTR RNAs with yet unknown functions.

neuroscience↗