LRH‐1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistanceMichalek, Svenja; Goj, Thomas; Plazzo, Anna Pia; Marovca, Blerim; Bornhauser, Beat; Brunner, Thomas
doi: 10.15252/embr.202154195pmid: 35801407
Nuclear receptors are transcription factors with important functions in a variety of physiological and pathological processes. Targeting glucocorticoid receptor (GR) activity using glucocorticoids is a cornerstone in the treatment of patients with T cell acute lymphoblastic leukemia (T‐ALL), and resistance to GC‐induced cell death is associated with poor outcome and a high risk for relapse. Next to ligand‐binding, heterodimerization with other transcription factors presents an important mechanism for the regulation of GR activity. Here, we describe a GC‐induced direct association of the Liver Receptor Homolog‐1 (LRH‐1) with the GR in the nucleus, which results in reciprocal inhibition of transcriptional activity. Pharmacological and molecular interference with LRH‐1 impairs proliferation and survival in T‐ALL and causes a profound sensitization to GC‐induced cell death, even in GC‐resistant T‐ALL. Our data illustrate that direct interaction between GR and LRH‐1 critically regulates glucocorticoid sensitivity in T‐ALL opening up new perspectives for developing innovative therapeutic approaches to treat GC‐resistant T‐ALL.
Transient upregulation of IRF1 during exit from naive pluripotency confers viral protectionRomeike, Merrit; Spach, Stephanie; Huber, Marie; Feng, Songjie; Vainorius, Gintautas; Elling, Ulrich; Versteeg, Gjis A; Buecker, Christa
doi: 10.15252/embr.202255375pmid: 35852463
Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation and the innate immune response. However, the expression of these interferon‐stimulated genes (ISG) in stem cells is independent from external stimuli such as viral infection. Here, we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and transiently upregulated during the transition from naive to formative pluripotency. IRF1 binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression upon exit from naive pluripotency. We show that in the absence of IRF1, cells exiting the naive pluripotent stem cell state are more susceptible to viral infection. Irf1 therefore acts as a link between the formative pluripotency network, regulation of innate immunity genes, and defense against viral infections during formative pluripotency.
Transient rapamycin treatment during developmental stage extends lifespan in Mus musculus and Drosophila melanogasterAiello, Giuseppe; Sabino, Cosimo; Pernici, Davide; Audano, Matteo; Antonica, Francesco; Gianesello, Matteo; Ballabio, Claudio; Quattrone, Alessandro; Mitro, Nico; Romanel, Alessandro; Soldano, Alessia; Tiberi, Luca
doi: 10.15252/embr.202255299pmid: 35796299
Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time window is involved in lifespan regulation. We also find that sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and in Drosophila larvae, and transient dST1 overexpression in Drosophila larvae extends lifespan. Our findings unveil a novel link between early‐life treatments and long‐term effects on lifespan.
Stepwise pluripotency transitions in mouse stem cellsEndoh, Mitsuhiro; Niwa, Hitoshi
doi: 10.15252/embr.202255010pmid: 35903955
Pluripotent cells in mouse embryos, which first emerge in the inner cell mass of the blastocyst, undergo gradual transition marked by changes in gene expression, developmental potential, polarity, and morphology as they develop from the pre‐implantation until post‐implantation gastrula stage. Recent studies of cultured mouse pluripotent stem cells (PSCs) have clarified the presence of intermediate pluripotent stages between the naïve pluripotent state represented by embryonic stem cells (ESCs—equivalent to the pre‐implantation epiblast) and the primed pluripotent state represented by epiblast stem cells (EpiSCs—equivalent to the late post‐implantation gastrula epiblast). In this review, we discuss these recent findings in light of our knowledge on peri‐implantation mouse development and consider the implications of these new PSCs to understand their temporal sequence and the feasibility of using them as model system for pluripotency.
Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's diseaseQu, Lili; Lin, Bingqian; Zeng, Wenping; Fan, Chunhong; Wu, Haotian; Ge, Yushu; Li, Qianqian; Li, Canjun; Wei, Yanan; Xin, Jing; Wang, Xingbing; Liu, Dan; Cang, Chunlei
doi: 10.15252/embr.202153234pmid: 35913019
Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl‐2 binds to and inhibits TMEM175 activity. Accordingly, Bcl‐2 inhibitors activate the channel in a caspase‐independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175‐mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).
Sequestration of LINE‐1 in cytosolic aggregates by MOV10 restricts retrotranspositionArora, Rajika; Bodak, Maxime; Penouty, Laura; Hackman, Cindy; Ciaudo, Constance
doi: 10.15252/embr.202154458pmid: 35856394
LINE‐1 (L1) retroelements have retained their ability to mobilize. Mechanisms regulating L1 mobility include DNA methylation in somatic cells and the piRNA pathway in the germline. During preimplantation stages of mouse embryonic development, however, both pathways are inactivated leading to a window necessitating alternate means of L1 regulation. We previously reported an increase in L1 levels in Dicer_KO mouse embryonic stem cells (mESCs), which was accompanied by only a marginal increase in retrotransposition, suggesting additional mechanisms suppressing L1 mobility. Here, we demonstrate that L1 ribonucleoprotein complexes (L1 RNP) accumulate as aggregates in the cytoplasm of Dicer_KO mESCs along with the RNA helicase MOV10. The combined overexpression of L1 ORF1p and MOV10 is sufficient to create L1 RNP aggregates. In Dicer_KO mESCs, MOV10 is upregulated due to the loss of its direct regulation by miRNAs. The newly discovered posttranscriptional regulation of Mov10, and its role in preventing L1 retrotransposition by driving cytosolic aggregation, provides routes to explore for therapy in disease conditions where L1s are upregulated.