Morphogenesis, the process by which cells, tissues, and organs acquire and maintain their form, is essential for embryogenesis, regeneration, and disease progression. During morphogenesis, cells within tissues dynamically interact with biophysical and biochemical signals from their environment by modifying their shape, gene expression, and function. These modifications often lead to transitions between cell states, and with that, to the establishment of functional programs that will in turn define embryonic stages or tissue states. Here, we discuss how the interplay of gene expression programs, chromatin modifications, and biophysical factors from the microenvironment contributes to the robust coordination of morphogenesis by allowing cells within tissues to dynamically transit across functional stages. This review summarizes the current knowledge on molecular regulation of cell and tissue state transitions in development and regeneration.
The tumor suppressor KDM6A/UTX, a histone demethylase and a 2-oxoglutarate-dependent dioxygenase, is frequently lost in many cancer types. We show that KDM6A loss pervasively activates oxidative phosphorylation in several solid tumors, generating a pseudo-hyperoxic environment, opposite from the pseudo-hypoxia observed in VHL-mutated renal carcinomas. Mechanistically, KDM6A sustains the expression of the coil-coil domain gene CCDC3, which inhibits CREB1-driven transcription of the mitochondrial regulator PPARGC1A. In the hematological cancer multiple myeloma where KDM6A is frequently deleted, its loss similarly promotes oxidative phosphorylation, but via an alternative mechanism: the increased transfer of mitochondria from stromal to myeloma cells via tunneling nanotubes, triggered by the loss of the mTORC1 inhibitor TRAF3IP3. Beyond cancer, KDM6A regulates oxidative phosphorylation also during development and in adult tissues, engaging either the CCDC3-CREB1 or the TRAF3IP3-mTORC1 pathways. These mutually exclusive associations suggest a tissue-level convergent evolution, positioning KDM6A as a central modulator of mitochondrial activity through context-specific partners. Loss of the oxygen-sensing chromatin regulator KDM6A/UTX is frequent in cancer cells. Here, this is shown to promote a pseudo-hyperoxic metabolic state through alternative tissue-specific pathways for controlling oxidative phosphorylation, highlighting tissue-level convergent evolution as a mechanism of metabolic regulation. Loss of the oxygen-sensing chromatin regulator KDM6A drives a pseudo-hyperoxic metabolic state through two pathways, one based on increased mitochondria synthesis, and another via increased mitochondria trafficking from stromal cells to cancer cells.
The study of Alzheimer’s disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of endogenous APP metabolite levels suggests a role for APP-CTFs, in particular APP-CTFβ, in regulating glutamatergic synaptic transmission. Presynaptic accumulation of APP-CTFβ promotes its oligomerization, increases synaptic vesicle docking, and causes vesicle release defects, accompanied by enhanced neuronal network activity. Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons. Strikingly, acute application of Aβ preparations enriched in monomeric species counteracts APP-CTFβ-induced hyperexcitability. Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer’s disease. Dysregulation of amyloid precursor protein (APP) proteolysis is involved in Alzheimer’s disease. This study shows that APP processing generates functionally distinct intermediates at the synapse, i.e. presynaptic APP-CTFβ, accumulation of which causes neuronal network hyperactivity, and extracellular amyloid-β (Aβ), which can counteract APP-CTFβ-induced network hyperactivity. APP-CTFβ, the precursor of amyloid-β, can accumulate in the active zone of excitatory synapses and promote neuronal network excitation/inhibition imbalance.
Paneth cells (PCs) are secretory cells in the small intestine with functions in intestinal homeostasis and innate immunity, with recent studies showing their ability to dedifferentiate and contribute to epithelial regeneration after injury. In this issue of The EMBO Journal, Yang et al, (2026) identify reactive oxygen species (ROS) as a central determinant of PC identity and uncover the Rho-family GTPase CDC42 as a critical regulator of this process. A recent study identifies CDC42 as a regulator of ROS-balance-dependent Paneth cell identity and antimicrobial function.
Perforin-2 is a pore-forming protein localised to the endocytic compartments of dendritic cells and macrophages. It is reported to perform two distinct functions during immune responses: attacking intravacuolar pathogens, and forming pores in endocytic compartments to enable cytosolic delivery of antigens during cross-presentation. The molecular mechanisms that regulate perforin-2 remain unknown. Here, we address how cross-presenting dendritic cells control pore formation in phagosomes while maintaining the integrity of their endocytic compartments. We demonstrate that perforin-2 undergoes extensive proteolytic processing involving multiple endocytic proteases. Although the transmembrane anchor has been proposed to protect host membranes by orienting pores towards bacterial targets, we find that endocytic escape is mediated by full-length, membrane-anchored perforin-2 rather than by the proteolytically released ectodomain. Moreover, we show that perforin-2-mediated antigen translocation does not require low pH, explaining how perforin-2 can form pores in cross-presenting dendritic cells which do not acidify their phagosomes. Our findings point to a critical role of the transmembrane anchor in perforin-2 biology and suggest that perforin-2 employs distinct mechanisms of pore formation during anti-bacterial defence and cross-presentation. Perforin-2 forms pores with functions in anti-bacterial immunity and in antigen delivery into the cytosol during cross-presentation. This study shows that perforin-2 undergoes extensive proteolytic processing, but its full-length form mediates antigen trafficking in dendritic cells. Perforin-2 employs distinct mechanisms of pore formation during anti-bacterial defence and antigen cross-presentation.
Target-directed microRNA degradation (TDMD) is an emerging post-transcriptional mechanism that controls miRNA turnover, yet its role in human cancers remains largely unexplored. Here, we combine CRISPRi-mediated ZSWIM8 depletion, miRNA-seq, and AGO2-eCLIP to define the TDMD landscape across breast cancer subtypes. We identify 19 high-confidence TDMD substrates, including miR-29b-3p and miR-33a/b-5p, and show that TDMD shapes miRNA target occupancy and target repression. Integration with single-cell transcriptomics reveals that TDMD of miR-29b-3p triggered by NREP transcript is associated with transcriptional plasticity along the epithelial–mesenchymal axis and marks a stem-like subpopulation of malignat cells with tumor-initiating potential in triple-negative breast cancer. Unexpectedly, we also uncover a non-canonical TDMD mechanism, independent of ubiquitin ligase ZSWIM8 and the proteasome, which includes SERPINE1-triggered miR-30c-5p degradation, conferring paclitaxel resistance and enhancing sphere-forming potential. These findings establish target-directed microRNA degradation as a functional layer of miRNA regulation in cancer, linking miRNA decay to cellular state transitions and therapeutic response. Our results broaden the mechanistic spectrum of TDMD and provide a framework to investigate how regulated miRNA decay contributes to aggressive breast cancer phenotypes. Target-directed microRNA degradation (TDMD) is an emerging post-transcriptional mechanism that controls miRNA turnover, yet its role in cancer remains largely unexplored. This study maps endogenous TDMD substrates across human breast cancer cell models and highlights the impact of TDMD on miRNA function in malignant cell plasticity via canonical and non-canonical mechanisms. A novel catalogue of decay-regulated microRNAs in breast cancer highlights direct roles for target directed miRNA degradation malignant cell plasticity.
Neoepitope-based therapies hold great promise for cancer immunotherapy because they target tumor-specific mutations and elicit potent anti-tumor T-cell responses. However, their clinical implementation remains limited by the complexity of neoepitope discovery and uncertainty regarding presentation by tumor cells. A potential alternative is the generation of immunogenic neoepitopes directly within cancer cells through programmable RNA editing. Here, we develop Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs that harness endogenous ADAR1 to direct precise adenosine-to-inosine (A-to-I) editing at selected transcript sites. Using these gRNAs, we demonstrate the generation of immunogenic neoepitopes through RNA editing at the transcript level, termed editopes. In a proof-of-concept model based on the melanoma antigen MART-1, SPEAR-mediated RNA editing restored antigen-specific T cell recognition and enabled tumor control in vivo. Finally, we developed a computational pipeline to identify candidate tumor-selective neoepitopes across multiple cancer types amenable to guided RNA editing. Our findings establish programmable RNA editing as a strategy for engineering immunogenic editopes and provide a framework for neoepitope-directed cancer immunotherapy. Clinical implementation of neoepitope-based cancer immunotherapy remains limited by challenges with neoepitope identification and presentation by tumor cells. This study develops Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs, a programmable RNA editing platform that harnesses endogenous ADAR1 to generate immunogenic neoepitopes at the transcript level (“editopes”), and uses them to enable antigen-specific T cell recognition in vitro and tumor control in vivo. The new RNA editing platform enables recruitment of endogenous ADAR1 to generate immunogenic neoepitopes at the transcript level (“editopes”).
VCP/p97 is an AAA+ ATPase that, together with its cofactors UFD1-NPL4 (p97-UN), unfolds ubiquitylated substrates to maintain cellular homeostasis. The human p97-UN complex associates with additional cofactors, but how these cofactors modulate p97-UN activity is not fully understood. Here, we screen cofactors and identify FAF2 to potently enhance substrate unfolding by p97-UN. Using biochemical and structural approaches, we show how FAF2 engages p97-UN and polyubiquitin to promote unfolding. We define a conserved activation motif in FAF2 that contacts both UFD1 and the ubiquitin proximal to the initiator, thereby stabilizing and supporting the unfolding of the initiator ubiquitin in a UFD1-dependent manner. We leverage the features of the FAF2 activation motif to engineer de novo proteins that potently enhance unfolding, providing a rational strategy to boost p97 activity. Our findings reveal how cofactors can provide additional adaptive control, fine-tuning human p97 activity to unfold challenging substrates and those modified with short ubiquitin chains. Efficient unfolding by the ATPase p97/VCP is essential for protein quality control, yet human p97 is far less efficient than its yeast counterpart for reasons that have remained unclear. This work investigates the cofactor and the mechanism enabling efficient unfolding by the human enzyme. A cofactor screen identifies FAF2 as the strongest activator of substrate unfolding by the human p97-UFD1-NPL4 complex.
Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel highly expressed in the skin and intestine. While its roles in itch and skin inflammation are established, the physiological role of TRPV3 in the intestine remains relatively poorly understood. Topical application of a TRPV3 inhibitor, KM-001, has entered phase I clinical trials for the treatment of pruritus; however, its poor metabolic stability limits broader therapeutic application. Here, we show that the KM-001-derivative Colivin has comparable TRPV3-blocking activity, but enhanced metabolic stability and increased oral bioavailability. Cryo-EM and site-directed mutagenesis analyses established that Colivin binds to the vanilloid binding pocket of TRPV3, stabilizing one of two distinct non-conducting conformations. Oral administration of Colivin effectively suppressed DSS-induced ulcerative colitis (UC) in wild-type, but not Trpv3-deficient mice. Collectively, our findings establish TRPV3 inhibition as a novel therapeutic strategy for UC, offer key structural insights into the inhibition mechanism of TRPV3, and provide critical structural insights for the rational design of potent and selective TRPV3 inhibitors. TRPV3 drives itch and inflammation in the skin, but is also widely expressed in the intestine where its function is unclear. This study identifies orally available Colivin as a TRPV3 inhibitor and key regulator of intestinal inflammation, suggesting intestinal TRPV3 inhibition as a promising therapeutic strategy for ulcerative colitis. Structural trapping reveals TRPV3 to be a druggable driver of intestinal inflammation.
Multicellular cyanobacteria have evolved sophisticated cell–cell communication machinery to exchange, synchronize, and coordinate the efforts of individual cells. Analogous to gap junctions that have traditionally been regarded as a eukaryotic feature, multicellular cyanobacteria coordinate their cell–cell communication via septal junctions (SJs). However, the signals that regulate cell–cell communication and septal-junction assembly are largely unknown. Lately, calcium signaling has been implicated in regulating cell junctions in eukaryotes. We recently discovered a Ca2+-binding protein, CSE, which is exclusively found in multicellular cyanobacteria. Here, we investigate CSE as a potential link between calcium signaling and cell–cell communication. We solve the NMR structure of CSE in its Ca2+-bound state and revealed that CSE acts as Ca2+-buffer protein. Using cryo-electron tomography, we find that Δcse mutant cells display significantly fewer septal junctions as well as SJ precursors known as nanopores. This indicates that CSE is not only essential for Ca2+ homeostasis, but also mediates cell–cell communication via regulating SJs and nanopores formation, and establishes Ca2+ signaling and CSE as key players regulating cyanobacterial multicellularity. Furthermore, these findings highlight calcium signaling as a conserved principle for regulating cellular junctions in organisms that diverged a billion years ago. Multicellular cyanobacteria like Nostoc sp. PCC 7120 build long filaments consisting of connected neighboring cells that exchange molecules through so-called septal junctions. This study shows that loss of the small calcium-binding protein CSE causes disruption of septal junctions and filament fragmentation. Loss of CSE in cyanobacterium Nostoc sp. PCC 7120 reveals calcium signaling as an evolutionarily conserved regulator of multicellularity and cell-cell junctions.
Macrophages can adopt diverse functional states in response to environmental cues, a process that is fundamentally controlled at the level of transcriptional regulation. In this review, we outline a hierarchical framework of transcription factor activity that underpins macrophage identity and activation. Firstly, lineage-determining transcription factors establish the cell-type-specific chromatin landscape during development. Upon tissue seeding, local signals shape the activity of additional transcription factors that refine enhancer landscapes and drive tissue-specific macrophage phenotypes. Macrophages further adopt their functional states when exposed to potential threats to tissue homeostasis, such as bacterial ligands or inflammatory cytokines. In response, signal-dependent transcription factors are activated and initiate signal-appropriate transcriptional programs. The specificity and durability of these responses are determined by secondary transcription factors that modulate the magnitude, timing, and maintenance of stimulus-induced transcriptional programs. Collectively, macrophage responses emerge from the activity of interconnected layers of cell-type-, tissue-, and signal-dependent transcription factors, forming complex regulatory networks that inflict stimulus-specific outcomes. Dysregulation of these networks can transcriptionally rewire macrophages toward disease-associated states. Delineating transcriptional regulators that distinguish signal responses may enable more targeted disease interventions. This review discusses how different layers of transcription factor activity cooperate to yield stimulus-specific macrophage responses.
Transcriptional co-activator complexes play essential roles in regulating gene transcription by integrating signals from transcription factors and chromatin. Among these, the SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada Two-A Containing) complexes represent related histone acetyltransferase assemblies that contain both shared and specific subunits. SAGA and ATAC possess similar and divergent enzymatic activities that shape their contributions to transcriptional control. Here, we review emerging evidence that highlights differential interactions of transcriptional activators with SAGA or ATAC and their differential chromatin-reading capabilities through specific recognition of histone modifications. Distinct requirements for SAGA and for ATAC have been observed in gene regulation important for maintaining cellular homeostasis and for oncogenic transformation, indicating that dysregulation of these complexes can contribute to cancer progression. The development of small-molecule inhibitors targeting key components of SAGA and/or ATAC offers promising strategies to disrupt their recruitment and transcriptional activity in cancer cells. Our review dissects the unique and overlapping functions of SAGA and ATAC, which are crucial for understanding regulation by these complexes in order to exploit them as targets in precision oncology. This review summarizes current understanding of how the SAGA and ATAC co-activator complexes regulate transcription through complementary molecular mechanisms and discusses opportunities for their therapeutic targeting in cancer.
Cells and tissue integrity are constantly challenged by the necessity to adapt and respond to mechanical loads. Among cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. Here we investigate whether the mechanical properties of chromatin and its organization into condensates contribute to nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we find that the balancing of transcriptional and Polycomb condensates tunes nuclear responsiveness to external mechanical forces. MLL4 assembles into mechanosensitive condensates through its prion-like domain, and this response is regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome, persistent nuclear envelope rupture triggers cGAS-STING activation, leading to programmed cell death. Together, these findings identify chromatin condensates as active regulators of nuclear mechanosensing and establish a mechanistic link between defective chromatin organization and cGAS–STING activation in Kabuki syndrome. Besides contributing to genome function, chromatin condensates are active components of the nuclear mechano-response. This study shows that the histone methyltransferase MLL4 functions as a chromatin mechano-sensor that preserves nuclear integrity and restrains cGAS-STING signalling during mechanical stress. Mechanical stress remodels chromatin condensates through MLL4 to preserve nuclear integrity and suppress cGAS–STING activation.
Cytoplasmic lattices (CPLs) are filamentous assemblies essential for mammalian embryonic development. They are known to regulate organelle organization, spindle assembly, and protein homeostasis, but their molecular functions remain unclear. Here, we develop a strategy combining cryo-focused ion beam milling and cryo-electron tomography to resolve macromolecular complexes directly in mammalian embryos. Using this approach, we determine the in situ structure of cytoplasmic lattices within 6/8-cell mouse embryos at 4.7 Å resolution. CPL filaments are built from multiple copies of at least fourteen proteins arranged into a 4.5 MDa repeating unit. The repeat contains a central cavity that is open at the back and lined with multiple FBXW–SKP1 complexes and three modules, each containing the E2 ubiquitin-conjugating enzyme UBE2D and the E3 ligase UHRF1. We resolve two CPL states: one is consistent with a ubiquitin-charged UBE2D, where ubiquitin is held in an open, inactive conformation by binding the scaffold protein PADI6; the second lacks discernible ubiquitin density and shows structural changes compatible with ubiquitin becoming available for transfer. Our findings support a model in which CPLs function as large ubiquitin ligase assemblies during early embryonic development. Cytoplasmic lattices (CPLs), abundant filamentous assemblies within mammalian oocytes and early embryos, are essential for development, yet their composition and function remain unclear. Here, in-situ cryo-electron tomography solves the structure of CPLs within 6/8-cell mouse embryos and reveals their involvement in regulation of ubiquitination. Structures of cytoplasmic lattices from early mouse embryos reveal the presence of ubiquitin conjugation complexes in two conformational states.
Inositol is an essential nutrient for most living organisms, as combinatorial phosphorylation on this cyclic sugar generates key cellular messengers, such as lipid-bound phosphoinositides (PtdInsPs), water-soluble inositol phosphates (InsPs), and high-energy inositol pyrophosphates (PP-InsPs). Although the kinases and phosphatases modifying inositol-derived molecules are well-characterised, the molecular pathways controlling the cellular homeostasis of the inositol backbone and transport carriers remain unclear. Using a combination of LC-MS analysis and a screen based on the inositol-exporting opi1Δ mutant yeast, we here discovered that inositol export is tightly regulated by PP-InsPs and that the high-affinity phosphate transporter Pho84 also acts as an inositol exporter. We further expanded these observations to the mammalian system and revealed that inositol export in human cells is similarly controlled by PP-InsPs, and that the human homolog of the yeast Pho84, GLUT2, contributes to inositol export. In summary, we discovered an evolutionarily conserved crosstalk pathway linking PP-InsPs to both phosphate and inositol homeostasis. Inositol provides the backbone for phosphoinositide and inositol phosphate signalling molecules, yet how cells regulate their pool of free inositol remain ill-defined. This study identifies yeast Pho84 and its human homologue GLUT2 as inositol exporters and uncovers inositol pyrophosphates as novel regulators of inositol homeostasis. An evolutionarily conserved transport circuit links inositol pyrophosphate signalling to cellular inositol and phosphate homeostasis.
Ion channels possess selectivity filters that are hardwired to ensure the selective passage of ions. Lysosomal two-pore channels are unusual as they are able to switch their cation selectivity in an agonist-specific manner, allowing differential control of organellar activity. TPC2 is permeable to Ca2+ when activated by the calcium-mobilizing messenger NAADP, but largely Na+-selective when activated by the signaling lipid PI(3,5)P2. Co-stimulation increases Ca2+ but not Na+ permeability; however, the molecular basis for these specificity switches is not well understood. Here we show that mutation of TPC2 residues within the distal cytosolic linker, which connects the first voltage-sensing-like domain to the pore, rendered TPC2 largely unable to discriminate its agonists and highly calcium-permeable, even in the presence of PI(3,5)P2. This mutation induced a co-activated-like state by disrupting a network of residues that connects the linker to the activation gate. Such deregulated agonist action increased lysosomal Ca2+ flux and compromised locomotion and viability when expressed in C. elegans. A proximal disease-linked mutation perturbed agonist action in a similar way both in vitro and in vivo. Biased signaling through TPC2 thus proceeds through molecular determinants that are remote from the selectivity filter, affecting Ca2+ permeability, endo-lysosomal integrity and disease. The selectivity of lysosomal TPC2 ion channels for either Ca²⁺ or Na⁺ depends on which agonists activate the channel. This article shows that this plasticity is governed by a distal allosteric network that allows TPC2 to discriminate between agonists and generate specific lysosomal ion fluxes. A distal allosteric network controls agonist-specific ion selectivity.
Progressive aging of bone marrow hematopoietic stem cells (HSCs) underlies clonal hematopoiesis and age-associated hematologic disorders. Defining early molecular events driving HSC functional decline is essential for rejuvenation strategies. Here, we identify P-selectin (Selp) as a surface marker that stratifies HSCs into conserved functional and transcriptional states during organismal aging in humans and mice. P-selectin expression increases early during aging and remains elevated in old HSCs. Selphigh-HSCs exhibit increased DNA damage and bias towards megakaryocytic/myeloid lineage fate, whereas Selplow-HSCs maintain metabolic integrity, enhanced antioxidant capacity, and reduced myeloid skewing. Transcriptomic analysis revealed that Selphigh-HSCs adopt megakaryocytic-primed, pro-inflammatory, and oxidative stress programs, while Selplow-HSCs retain lymphoid-associated and redox-balanced signatures consistent with a more preserved stem-cell state. Further ATAC-seq analysis demonstrates distinct chromatin landscapes with Selphigh-HSCs being enriched for inflammatory and platelet-related regulatory elements and CTCF motifs, but Selplow-HSCs displaying accessible ETS-driven networks linked to metabolic fitness and stem cell resilience. Together, these findings uncover conserved heterogeneity during blood stem cell aging and establish P-selectin as an early biomarker and potential therapeutic target to mitigate age-associated hematopoietic decline. This study identifies P-selectin (Selp) as an evolutionarily conserved surface marker that captures functional and transcriptomic heterogeneity within the elderly hematopoietic stem cell (HSC) compartment. Early aged HSC pools are stratified by Selp expression levels into functionally divergent populations, driven by separate transcriptional programs and chromatin landscapes. P-selectin captures distinct functional and transcriptomic states in aged blood stem cells.
Tissue regeneration after injury is crucial for restoring epithelial structure and function. Upon damage, a regenerative microenvironment forms that provides signalling cues that stimulate stem cell proliferation to replace lost cells. While this process is well understood, how stem cells themselves sense damage, translate this input into their proliferation and shape the regenerative microenvironment remains unclear. Here we show that Draper-Src-Shark signalling in Drosophila intestinal stem cells (ISCs) recognises tissue damage by sensing externalised phosphatidylserine on dying midgut epithelial cells and is required for STAT activation in ISCs to promote their proliferation. Unlike its role in phagocytosis, Draper in ISCs does not promote the clearance of these apoptotic enterocytes but rather facilitates ISC proliferation in the presence of damaged enterocytes. Moreover, Draper-Src-Shark signalling in progenitors regulates STAT transcriptional activity in the adjacent visceral muscle, indicating that progenitors can shape the regenerative microenvironment beyond tissue boundaries. As Src and STAT are also activated in the mammalian intestinal epithelium after damage and tumour formation, these findings may help develop therapies for tissue regeneration, inflammatory diseases and cancer. Somatic stem cell proliferation after damage is thought to rely mainly on proliferative cues from the regenerative microenvironment. This study shows that adult Drosophila intestinal stem cells (ISCs) directly sense damage to facilitate their own proliferation and shape local tissue responses. Somatic stem cells in the gut directly sense damage to facilitate proliferation and tissue recovery.
Abstract The Wnt family ligands carry a lipid moiety that must be shielded from the aqueous environment. During secretion, this is achieved by the cargo receptor Wntless. The effect of acute endocytosis inhibition suggests that Wingless dissociates from Wntless at the apical plasma membrane but is prevented from being released extracellularly by rapid endocytosis. Super-resolution microscopy shows that Wingless then traffics, without Wntless, through specialized Rab7/Rab4-positive endosomes before basolateral release. In the absence of endocytosis, apical release is allowed, albeit in punctae. Similar punctae are formed upon abrogation of the ceramide synthase Schlank. We suggest that they represent insoluble aggregates since they are ‘solubilized’ by the lipid-binding protein Dally-like protein. Moreover, purified Wingless forms similar-looking structures that are solubilised by liposomes in vitro. These findings suggest that membrane lipid composition could modulate the stability of the Wingless–Wntless complex and/or the lipid bilayer’s ability to accommodate the Wingless lipid. Together with rapid endocytosis, this ensures orderly transfer of Wingless from Wntless to the membrane, preventing aggregation, and promoting basolateral secretion.
