EMBO Reports最新文献

Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacetylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting its degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit increased global protein synthesis in the hearts, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression reduces global protein synthesis in the hearts of SIRT2 transgenic mice. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation could be a potential therapeutic strategy for treating diseases associated with increased protein synthesis.

RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4's functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4^fl allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.

Glial cells are crucial for nervous system development and function by clearing debris, protecting neurons and ensuring neuronal survival. In Drosophila, glia form the blood-brain barrier, which regulates neural stem cell proliferation and shields the nervous system while maintaining communication with the rest of the organism. To uncover glial-specific roles, we here compare their transcriptome with that of neurons and macrophages. Our study identifies NimA, an uncharacterized member of the Nimrod family, as a glial-specific protein expressed during development. Unlike other family members (i.e. NimC1, Draper and NimC4/Simu) NimA is not involved in phagocytosis. Instead, NimA regulates cell-cell adhesion, crucial for maintaining the tight septate junctions of the larval BBB. Loss of NimA in BBB-forming glia compromises barrier integrity. Moreover, loss of NimA in those glia, or in glia that serve as neural stem cell niche, delays development, reduces brain size, impairs proliferation and reduces the neural stem cell pool. The identification of the glial-specific molecular landscape, including novel molecular players such as NimA, is key for understanding the contribution of glia to the nervous system.

IRF2 plays an indirect role in inflammasome activation by regulating Caspase-4 and Gasdermin D (GSDMD) levels. However, the in vivo relevance of this regulatory circuit is unknown. We generate IRF2^KO mice and demonstrate that they are equally susceptible to Francisella novicida infection as GSDMD^KO mice. Interestingly, the phenotypes of IRF2^KO and GSDMD^KO mice diverge with respect to IFN-γ. Specifically, IRF2^KO mice exhibit a profound defect in IFN-γ production, which we attribute to an intrinsic role of IRF2 in regulating both the number and maturation of NK cells. IRF2^KO NK cells fail to express the antibacterial effectors IL-18R and Granzyme A, thereby impairing bacterial clearance. IFN-γ therapy partially restores immune responses in IRF2^KO mice and resistance to infection. These findings confirm IRF2 as a dual regulator of inflammasome activity and NK cell function, highlighting its pivotal role in innate immunity. Moreover, they underscore the potential of IFN-γ therapy as a promising treatment for severe infections in patients with primary immunodeficiencies affecting multiple immune pathways.

The Drosophila Toll/NF-κB pathway has been extensively studied for its roles in innate immunity and embryonic development. Nevertheless, the regulatory mechanisms underlying Spz/Toll signaling in non-immune contexts remain poorly understood. Here, we demonstrate a critical role for Toll in regulating intestinal stem cell activity through direct transcriptional control of PI3K and Akt in an insulin-independent manner. Time-series transcriptomic analysis of intestinal damage and repair responses reveals that the stress-responsive factor Jumu regulates Spz expression to activate Toll signaling. Disruption of the Jumu/Spz/Toll cascade or PI3K/Akt signaling impairs intestinal regeneration and suppresses tumor growth, and epistasis analysis confirms that PI3K/Akt functions downstream of Toll. Our findings elucidate an autocrine Spz/Toll-mediated mechanism that drives stem cell function via the PI3K/Akt pathway during tissue homeostasis and uncover a critical non-immune role of Toll signaling in both physiological and pathological contexts.

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) is a critical cytosolic DNA sensor, whose activity can be regulated by acetylation. Here, we show that nicotinamide adenine dinucleotide (NAD⁺)-dependent lysine deacetylase SIRT4 interacts with cGAS and positively regulates innate immune responses triggered by DNA viruses or cytoplasmic DNA. Overexpression of SIRT4 inhibits HSV-1 infection, whereas knockdown of SIRT4 has the opposite effect. Deficiency of SIRT4, or treatment with a SIRT4 inhibitor, impairs antiviral innate immune signaling in response to DNA viruses or cytoplasmic DNA, both in vitro and in vivo. Moreover, SIRT4 inhibitor treatment attenuates type I interferon signaling in Trex1-deficient cells and in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). Mechanistically, SIRT4 deacetylates cGAS and enhances its association with double‑stranded DNA. Collectively, our study identifies SIRT4 as a positive regulator of cGAS-mediated innate immune signaling pathways, which advances the understanding of the regulation of cGAS activity.

Motile cilia are evolutionarily conserved protrusions critical for motility and homeostasis. Their rhythmic movements require the central pair microtubules (CP-MTs). While the initial CP-MT assembly in mammals is mediated by WDR47 and microtubule minus-end-binding CAMSAPs, the mechanism by which CP-MTs are stabilized remains unclear. Here, we demonstrate that WDR47 coordinates JHY and SPEF1 to maintain the stability of mammalian CP-MTs. By generating a proximity interactome of WDR47, we identify a group of CP-MT-associated proteins, including SPEF1 and JHY. WDR47 enriches JHY and SPEF1 to the central lumen and tip of nascent cilia, whereas SPEF1 recruits WDR47 and JHY to CP-MTs through direct interactions. Jhy deficiency in mice preferentially disrupts distal CP-MTs, resulting in rotatory ciliary beats. Phylogenetic analyses suggest conserved functions of WDR47 and SPEF1 in protozoa and metazoans, as well as a role for JHY in animals with radial or bilateral body symmetry. We propose that JHY emerges to further reinforce CP-MTs, enabling the transition from switchable to fixed ciliary waveforms in metazoan evolution.

Tissue damage activates immediate responses to restrict further harm and initiate repair. How injury sensing is coupled to regeneration is still not well understood. Here, we study regenerative responses in the adult Drosophila brain, where proliferation is normally strongly restricted. We show that localized brain damage triggers oxidative stress and diverse brain protective programs. We find that ROS generation by the NADPH Oxidase Duox in glial cells is responsible for injury-induced oxidative stress. Both genetic and chemical suppression of ROS in injured brains impairs regeneration. In particular, selective knockdown of calcium-sensitive Duox in glia, which show elevated calcium after injury, reduces injury-induced proliferation. We further provide evidence that diffusing ROS can sustain the activity of pro-regenerative signaling, which is required to stimulate cell divisions. Although oxidative stress is generally considered as harmful in the brain, we uncover here an unanticipated beneficial role of transient ROS release by glia to promote brain repair.