The EMBO Journal

Abstract Reactivation of quiescent neural stem cells (NSCs) in the central nervous system (CNS) is a tightly controlled process that generates new neurons and glia to maintain homeostasis or enable repair post-injury, but it remains unclear if reactivation of distinct NSC populations is coupled. Here, we discovered that NSC quiescence exit in Drosophila follows a hierarchical sequence, whereby ac…

Abstract The biogenesis and transport of lipoproteins are essential for systemic homeostasis and cardiometabolic health, yet how the secretory pathway acquires specialization to support high-capacity lipoprotein export remains unclear. Here, we report SEC16B as a tissue-selective modulator of the COPII machinery, critical for the efficient secretion of APOB-containing lipoproteins. Integrative bi…

Abstract CRISPR RNAs (crRNAs) guide recognition and targeting of intracellular invaders as part of adaptive immunity by CRISPR-Cas systems. crRNAs are transcribed from CRISPR arrays of conserved repeats interlaced with invader-derived spacers. While crRNA production is essential for immunity, its optimization for defense remains poorly understood. Here, we show that, in diverse RNA-targeting type…

Abstract The Mas1 receptor, an orphan class A G-protein-coupled receptor (GPCR), plays pivotal roles in cardiovascular and anti-inflammatory regulation. Despite its therapeutic relevance, the structural mechanisms underlying Mas1 ligand binding and activation remain poorly understood. Here, we report cryo-EM structures of Mas1 bound to two chemically distinct agonists—neuropeptide FF (NPFF) and s…

STING is an evolutionarily conserved key regulator of innate immunity. In the model organism Drosophila melanogaster, STING activates the NF-κB-like transcription factor Relish, initially characterized for its role in the antibacterial IMD pathway. The versatile FADD/Caspase-8 axis is widely used in various immune signaling pathways throughout the animal kingdom, including the IMD pathway. Here, …

Cdk5 regulatory subunit-associated protein 1-like 1 (Cdkal1) encodes a tRNA-modifying enzyme responsible for thiomethylation generating 2-methylthio-N⁶-threonylcarbamoyladenosine (ms²t⁶A) in the anticodon loop of tRNA^Lys_UUU. Genome-wide association studies have identified CDKAL1 variants as risk factors for type 2 diabetes mellitus (DM) and c…

Enzymes are generally believed to evolve from promiscuous ancestors to more specialized descendants under some selection pressure related to their function. However, enzymes whose function depends on substrate promiscuity have not been studied. Here, we show that a group of highly diverse, xenobiotic-metabolizing enzymes, responsible for defense against a constantly changing battery of xenobiotic…

Clearance of arrested nascent polypeptides resulting from ribosomal stalling is essential for proteostasis. Stalled endoplasmic reticulum (ER)-bound ribosomes are marked by ubiquitin-fold modifier 1 (UFM1) on the large ribosomal subunit protein RPL26, but the precise role of this modification in ribosome-associated quality control (RQC) remains poorly understood. Here, we define the interplay bet…

Membrane trafficking through the trans-Golgi network has been shown to guide activation of the NLRP3 inflammasome. Rab11 GTPases and their effector Rab11-FIP2 regulate endosomal trafficking and retrograde transport. Here, we demonstrate that Rab11b and Rab11-FIP2 contribute to NLRP3 and pro-IL-1β stabilization during the inflammasome priming phase, which is followed by inflammasome activation. We…

X-chromosome inactivation (XCI) balances gene expression between sexes in mammals and is essential to female development. XCI initiation strictly relies on the upregulation of long noncoding RNA Xist upon differentiation. Despite the co-occurrence and tight correlation between XCI and differentiation, master coordinators to synchronize XCI and differentiation remain ill-defined. Here, we report t…

The in vivo mechanism, cis-acting roadblocks, and biological functions of DNA loop extrusion by eukaryotic SMC complexes remain incompletely defined. Here, we identify condensin-dependent Hi-C contact stripes at the recombination enhancer (RE) and at rDNA in S. cerevisiae. The RE is an autonomous condensin loading site only active in MATa cells from which oriented, unidirectional loop extrusion p…

Enhanced P-TEFb activity is thought to promote cell proliferation by increasing the transcriptional output of RNA polymerase II. The 7SK snRNP complex, which contains LARP7 and HEXIM1, sequesters and inhibits most cellular P-TEFb to prevent premature transcription elongation. Paradoxically, instead of exerting overgrowth effects, biallelic inactivation of LARP7 is linked to Alazami syndrome, a hu…

ER-associated degradation (ERAD) targets misfolded proteins in the endoplasmic reticulum (ER) for proteasomal degradation. Mutations in its most conserved branch involving the SEL1L-HRD1 complex cause ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI), characterized by developmental delay, microcephaly, and locomotor dysfunction. Its most severe form, ENDI with agammaglobul…

Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca²⁺ leakage history with a newly developed Ca²⁺ probe in human macrophages, we discovered that Ca²⁺ leakage…

Ubiquilins are molecular chaperones that play multifaceted roles in proteostasis, with point mutations in UBQLN2 leading to altered phase-separation properties and amyotrophic lateral sclerosis (ALS). Our mechanistic understanding of this essential process has been hindered by a lack of structural information on the STI1 domain, which is essential for ubiquilin chaperone activity and phase separa…

Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR s…

During mitosis, properly aligned chromosomes stabilise microtubule ends with the help of kinetochores to ensure timely segregation of chromosomes. Microtubule-binding components of the human outer kinetochore, such as Ndc80 and Ska complexes, are present in multiple copies and together bind several microtubule ends, creating a highly multivalent binding interface. Whereas Ndc80:Ndc80 and Ndc80:mi…

The activation of the embryonic genome is a crucial step in development. In addition to thousands of genes, many transposable elements (TEs) are robustly transcribed during early mammalian development. However, their transcriptional regulators remain largely unexplored. Here, we set out to identify transcription factors regulating the expression of TEs from the LINE, SINE and ERVL families during…

Meiotic prophase I, characterized by homologous recombination and synapsis, is a critical step in spermatogenesis. This process entails extensive changes to chromatin and transcription. Prior to prophase I, accessible chromatin bound by paused Pol II at meiotic gene promoters is essential for their timely activation later during meiosis. However, the factors responsible for establishing accessibl…

The exceptional virulence of the human malaria parasite, Plasmodium falciparum, is attributed to the adhesive properties of infected red blood cells and the parasite's ability to avoid antibody recognition through antigenic variation. Both properties are derived from the hypervariable surface protein PfEMP1, which is encoded by members of the multi-copy var gene family. Waves of parasitemia durin…