Biology subjects

Frech, M.

Publications and source records attributed to Frech, M..

4 recordsLinked to original sources

bioRxiv2023

RETINOID ORPHAN RECEPTOR GAMMA T (RORgT) PROMOTES INFLAMMATORY EOSINOPHILIA BUT IS DISPENSABLE FOR INNATE IMMUNE-MEDIATED COLITIS

Inflammatory bowel diseases (IBD) result from uncontrolled inflammation in the intestinal mucosa leading to damage and loss of function. Both innate and adaptive immunity contribute to the inflammation of IBD and innate and adaptive immune cells reciprocally activate each other in a forward feedback loop. In order to better understand innate immune contributions to IBD, we developed a model of spontaneous 100% penetrant, early onset colitis that occurs in the absence of adaptive immunity by crossing villin-TNFAIP3 mice to RAG1-/- mice (TRAG mice). This model is driven by microbes and features increased levels of innate lymphoid cells in the intestinal mucosa. To investigate the role of type 3 innate lymphoid cells (ILC3) in the innate colitis of TRAG mice, we crossed them to retinoid orphan receptor gamma t deficient (Ror{gamma}t-/-) mice. Ror{gamma}t-/- x TRAG mice exhibited markedly reduced eosinophilia in the colonic mucosa, but colitis persisted in these mice. Colitis in Ror{gamma}t-/- x TRAG mice was characterized by increased infiltration of the intestinal mucosa by neutrophils, inflammatory monocytes, macrophages and other innate cells. RNA and cellular profiles of Ror{gamma}t-/- x TRAG mice were consistent with a lack of ILC3 and ILC3 derived cytokines, reduced antimicrobial factors, increased activation oof epithelial repair processes and reduced activation of epithelial cell STAT3. The colitis in Ror{gamma}t-/- x TRAG mice was ameliorated by antibiotic treatment indicating that microbes contribute to the ILC3-independent colitis of these mice. Thus, Ror{gamma}t promotes eosinophilia but Ror{gamma}t and Ror{gamma}t-dependent ILC3 are dispensable for the innate colitis in TRAG mice.

immunology↗

bioRxiv2023

IRF2BP2 counteracts the ATF7/JDP2 AP-1 heterodimer to prevent inflammatory overactivation in acute myeloid leukemia (AML) cells

Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may therefore represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

molecular biology↗

bioRxiv2022

Visualizing the Transiently Populated Closed-State of Human HSP90 ATP Binding Domain

HSP90 are abundant molecular chaperones, assisting the folding of several hundred client proteins, including substrates involved in tumor growth or neurodegenerative diseases. A complex set of large ATP-driven structural changes occurs during HSP90 functional cycle. However, the existence of such structural rearrangements in apo HSP90 has remained unclear. Here, we identified a metastable excited state in the isolated HSP90 ATP binding domain. We used solution NMR and mutagenesis to characterize structures of both ground and excited states. We demonstrated that in solution the HSP90 ATP binding domain transiently samples a functionally relevant ATP-lid closed state, distant by more than 30 [A] from the ground state. NMR relaxation and molecular dynamics were combined to characterize the energy landscape corresponding to the transition between these interconverting states. The precise description of the dynamics and structures sampled by human HSP90 ATP binding domain is a paramount piece of information for the future design of new therapeutic ligands.

biophysics↗

bioRxiv2022

Alcohol-sourced acetate reduces T cell filamentous actin branching and migration

Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart and brain. Alcohol also has strong immunoregulatory properties. Here we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescued the acetate-induced inhibition of T cell migration, primary mouse cortactin knock-out T cells exhibited impaired migration. Furthermore, acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.

immunology↗