EMBO Molecular Medicine最新文献

Patients with the rare genetic disorder Hyaline Fibromatosis Syndrome (HFS) often succumb before 18 months of age due to severe diarrhea. As HFS is caused by loss-of-function mutations in the gene encoding capillary morphogenesis gene 2 (CMG2), these symptoms highlight a critical yet unexplored role for CMG2 in the gut. Here, we demonstrate that CMG2 knockout mice exhibit normal colon morphology and no signs of inflammation until the chemical induction of colitis. In these conditions, the colons of knockout mice do not regenerate despite previously experiencing similarly severe colitis, due to an inability to replenish their intestinal stem cell pool. Specifically, CMG2 knockout impairs the transition from fetal-like to Lgr5+ adult stem cells, which is associated with a defect in ß-catenin nuclear translocation. Based on our findings, we propose that CMG2 functions as a context-specific modulator of Wnt signaling, essential for replenishing the pool of intestinal stem cells following injury. This study provides new insights into the molecular mechanisms underlying lethal diarrhea in HFS and offers a broader understanding of fetal-like regenerative responses.

The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1β secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1β release in macrophages, contributing to inflammatory arthritis in mice.

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.